Novel intermediates of cephalosporins and process for producing 7-(substituted or unsubstituted amino)-3-substituted methyl-Δ3 -cephem-4-carboxylic acids

ABSTRACT

This invention relates to novel 7-(substituted or unsubstituted amino)-3-substituted methyl-Δ 3  -cephem-4-carboxylic acids in which a substituted or unsubstituted 1,2,4-triazolyl or 2-(1,2,3,4-tetrazolyl) group attaches to the exomethylene group at the 3-position of the cephem ring through a carbon-nitrogen bond. These cephalosporins are useful intermediates for producing various novel cephalosporins. Also, this invention concerns a process for producing a compound represented by the formula: ##STR1## which comprises reacting a compound represented by the formula: ##STR2## with an optionally substituted triazole or tetrazole in the presence of an acid or a complex of the acid in an organic solvent at 0° to 80° C.

This is a division, of application Ser. No. 304,912, filed Sept. 23,1981, now U.S. Pat. No. 4,489,072.

This invention relates to novel cephalosporins, processes for producingsaid cephalosporins, intermediates for the production of saidcephalosporins, and a process for producing the intermediates.

The present inventors have conducted studies with the aim of discoveringcompounds having a broad antibacterial spectrum, exhibiting an excellentantibacterial activity to gram-positive and gram-negative bacteria,being stable to β-lactamase produced by bacteria, having a low toxicity,being at the same time well absorbable upon oral or parenteraladministration and having an excellent therepeutic effect on the humanand animal diseases. As a result, it has been found that novelcephalosporins characterized in that a substituted or unsubstitutedaryl, acylamino, aromatic teterocyclic, triazolyl or tetrazolyl group isattached to the exomethylene group at the 3-position of the cephem ring,said aromatic heterocyclic group being attached through a carbon-carbonbond and said triazolyl or tetrazolyl group being attached through acarbon-nitrogen bond, and the following group is attached to the aminogroup at the 7-position, have the above-mentioned excellent properties:##STR3## wherein A, R³ and R⁴ are as defined below.

It is objects of this invention to provide novel cephalosporins havingthe above-mentioned chemical structural characteristic features, toprovide novel cephalosporins having a broad antibacterial spectrum, toprovide novel cephalosporins stable against β-lactamase produced bybacteria, to provide novel cephalosporins having a low toxicity andbeing well absorbed upon oral or parenteral administration and toprovide novel cephalosporins having an excellent therapeutic effect onthe human and animal diseases.

It is further objects of this invention to provide a process forproducing said novel cephalosporins, to provide intermediates for theproduction of said novel cephalosporins and to provide a process forproducing said intermediates.

Other objects and advantages of this invention will become apparent fromthe following description.

The novel cephalosporins of this invention involve compounds representedby the formula [I] and salts thereof: ##STR4## wherein R¹ represents ahydrogen atom or a carboxyl-protecting group; R² represents asubstituted or unsubstituted aryl, acylamino, aromatic heterocyclic,triazolyl or tetrazolyl group, said aromatic heterocyclic group beingattached to the 3-exomethylene group through a carbon-carbon bond andsaid triazolyl or tetrazolyl group being attached to the 3-exomethylenegroup through a carbon-nitrogen bond; R³ represents a hydrogen orhalogen atom; R⁴ represents a hydrogen atom or an amino group which maybe protected or substituted; A represents a group of the formula, --CH₂--, or a group of the formula, ##STR5## in which R⁵ represents ahydrogen atom or an alkyl group and the bolt represents syn or antiisomer or their mixture; and B represents a hydrogen atom or a loweralkoxy group.

In this specification, unless otherwise specified, the term "alkyl"means straight or branched chain C₁₋₁₄ alkyl, for example, methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec.-butyl,tert.-butyl, pentyl, hexyl, heptyl, octyl, dodecyl and the like; theterm "alkoxy" means O-alkyl having the alkyl group defined above; theterm "lower alkyl" means straight or branched chain C₁₋₅ alkyl, forexample, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,sec.-butyl, tert.-butyl, pentyl and the like; the term "lower alkoxy"means --O--lower alkyl having the lower alkyl group defined above; theterm "acyl" means C₁₋₁₂ acyl, for example, acetyl, propionyl, butyryl,benzoyl, naphthoyl, pentanecarbonyl, cyclohexanecarbonyl, furoyl,thenoyl and the like; the term "acyloxy" means --O--acyl having the acylgroup defined above; the term "alkylthio" means --S--alkyl having thealkyl group defined above; the term "akenyl" means C₂₋₁₀ alkenyl, forexample, vinyl, allyl, isopropenyl, 2-pentenyl, butenyl and the like;the term "alkinyl" means C₂₋₁₀ alkinyl, for example, ethynyl, 2-propynyland the like; the term "cycloalkyl" means C₃₋₇ cycloalkyl, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and thelike; the term "alkadienyl" means C₄₋₁₀ alkadienyl, for example,1,3-butadienyl, 1,4-hexadienyl, and the like; the term "cycloalkenyl"means C₅₋₇ cycloalkenyl, for example, cyclopentenyl, cyclohexenyl andthe like; the term "cycloalkadienyl" means C₅₋₇ cycloalkadienyl, forexample, cyclopentadienyl, cyclohexadienyl and the like; the term "aryl"means, for example, phenyl, naphthyl, indanyl and the like; the term"aralkyl" means arlower alkyl, for example, benzyl, phenethyl,4-methylbenzyl, naphthylmethyl and the like; the term "heterocyclicgroup" means heterocyclic group having at least one hetero-atom selectedfrom the group consisting of oxygen, nitrogen and sulfur, for example,furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl,thiatriazolyl, oxatriazolyl, triazolyl, tetrazolyl, pyridyl,3-(2-methyl-4-pyrrolinyl), 3-(4-pyrrolinyl), N-(methylpiperidinyl),quinolyl, phenazinyl, 1,3-benzodioxolanyl, benzofuryl, benzothienyl,benzoxazolyl, benzothiazolyl, coumarinyl and the like; the term"heterocycle-alkyl" means a group consisting of a heterocyclic group asdefined above and an alkyl group as defined above; and the term "halogenatom" means fluorine, chlorine, bromine and iodine atoms.

In the formulas described herein, R₁ is a hydrogen atom or acarboxyl-protecting group. The carboxyl-protecting groups which haveconventionally been used in the penicillin and cephalosporin fields areavailable and include ester-forming groups which can be removed bycatalytic reduction, chemical reduction or other treatments under mildconditions; ester-forming groups which can easily be removed in livingbodies; and other known ester-forming groups which can easily be removedby treatment with water or an alcohol, such as organic silyl groups,organic phosphorus-containing groups, organic tin-containing groups, orthe like.

Examples of typical carboxyl-protecting groups are:

(a) Alkyl groups;

(b) Substituted lower alkyl groups, at least one of the substituents ofwhich is halogen, nitro, carboalkoxy, acyl, alkoxy, oxo, cyano,cycloalkyl, aryl, alkylthio, alkylsulfinyl, alkylsulfonyl,alkoxycarbonyl, 5-alkyl-2-oxo-1,3-dioxol-4-yl, 1-indanyl, 2-indanyl,furyl, pyridyl, 4-imidazolyl, phthalimido, succinimido, acetidino,aziridino, pyrrolidino, piperidino, morpholino, thiomorpholino,pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,thiadiazolyl, oxadiazolyl, thiatriazolyl, oxatriazolyl, triazolyl,tetrazolyl, pyridyl, quinolyl, phenazinyl, benzofuryl, benzothienyl,benzoxazolyl, benzothiazolyl, coumarinyl, N-lower alkylpiperazino,2,5-dimethylpyrrolidino, 1,4,5,6-tetrahydropyrimidinyl,4-methylpiperidino, 2,6-dimethylpiperidino, 3-(2-methyl-4-pyrrolinyl),3-(4-pyrrolinyl), N-(methylpiperidinyl), 1,3-benzodioxolanyl,alkylamino, dialkylamino, acyloxy, acylamino, acylthio,dialkylaminocarbonyl, alkoxycarbonylamino, alkenyloxy, aryloxy,aralkyloxy, alicycleoxy, heterocycle-oxy, alkoxycarbonyloxy,alkenyloxycarbonyloxy, aryloxycarbonyloxy, aralkyloxycarbonyloxy;alicycle-oxycarbonyloxy, heterocycle-oxycarbonyloxy, alkenyloxycarbonyl,aryloxycarbonyl, aralkyloxycarbonyl, alicycle-oxycarbonyl,heterocycle-oxycarbonyl, alkylanilino and alkylanilino substituted byhalogen, lower alkyl, or lower alkoxy;

(c) Cycloalkyl groups, lower-akyl-substituted cycloalkyl groups, or[2,2-di(lower alkyl)-1,3-dioxolan-4-yl]methyl groups;

(d) Alkenyl groups;

(e) Alkinyl groups;

(f) Phenyl group, substituted phenyl groups, at least one of thesubstituents of which is selected from the substitutents exemplified inabove (b); or aryl groups represented by the formula: ##STR6## wherein Xis --CH═CH--O--, --CH═CH--S--, --CH₂ CH₂ S--, --CH═N--CH═N--,--CH═CH--CH═CH--, --CO--CH═CH--CO--, or --CO--CO--CH═CH--, orsubstituted derivatives thereof, the substituents of which are selectedfrom those exemplified in above (b), or the formula: ##STR7## wherein Yis a lower alkylene group such as --(CH₂)₃ -- and --(CH₂)₄ --, orsubstituted derivatives thereof, the substituents of which are selectedfrom those exemplified in above (b);

(g) Aralkyl groups which may be substituted, at least one of thesubstituents of which is selected from those exemplified in above (b);

(h) Heterocyclic groups which may be substituted, at least one of thesubstituents of which is selected from those exemplified in above (b);

(i) Alicylic indanyl or phthalidyl groups or substituted derivativesthereof, the substituent of which is halogen or methyl; alicyclictetrahydronaphthyl groups, or substituted derivatives thereof, thesubstituent of which is halogen or methyl; trityl group, cholesterylgroup, or bicyclo[4,4,0]-decyl group.

(j) Alicyclic phthalidylidene-lower alkyl group or substitutedderivatives thereof, the substituent of which is halogen or lower alkoxygroup.

The carboxyl-protecting groups listed above are typical examples, andthere may be used any groups selected from those disclosed in U.S. Pat.Nos. 3,499,909; 3,573,296; and 3,641,018, West GermanOffenlegungsschrift No. 2,301,014; 2,253,287; and 2,337,105.

Among them, preferable carboxyl-protecting groups are those which canreadily be removed in living bodies such as 5-loweralkyl-2-oxo-1,3-dioxol-4-yl groups, acyloxyalkyl groups, acylthioalkylgroups, phthalidyl group, indanyl group, phenyl group, substituted orunsubstituted phthalidylidene-lower alkyl groups or groups representedby the formulas: ##STR8## wherein R⁶ represents a straight or branchedchain substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl,alicyclic, or heterocyclic group, R⁷ represents a hydrogen atom or analkyl group, R⁸ represents a hydrogen atom, a halogen atom or asubstituted or unsunstituted alkyl, cycloalkyl, aryl or heterocyclicgroup or --(CH₂)_(n) --COOR⁶ wherein R⁶ is as defined above and nrepresetns 0, 1 or 2, and m represents 0, 1 or 2.

The above-mentioned preferable carboxyl-protecting groups includespecifically 5-lower alkyl2-oxo-1,3-dioxol-.4-yl groups such as5-methyl-2-oxo1,3-dioxol-4-yl, 5-ethyl-2-oxo-1,3-dioxol-4-yl,5-propyl-2-oxo-1,3,-dioxol-4-yl, and the like; acyloxyalkyl groups, suchas acetoxymethyl, pivaloyloxymethyl, propionyloxymethyl,butyryloxymethyl, iso-butyryloxymethyl, valeryloxymethyl,1-acetoxy-ethyl, 1-acetoxy-n-propyl, 1-pivaloyloxy-ethyl,1-pivaloyloxy-n-propyl and the like; acylthioalkyl groups such asacetylthiomethyl, pivaloylthiomethyl, benzoylthiomethyl,p-chlorobenzoylthiomethyl, 1-acetylthio-ethyl, 1-pivaloylthio-ethyl,1-benzoylthio-ethyl, 1-(p-chlorobenzoylthio)-ethyl and the like;alkoxymethyl groups such as methoxymethyl, ethoxymethyl, propoxymethyl,isopropoxymethyl, butyloxymethyl and the like; alkoxycarbonyloxymethylgroups such as methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl,propoxycarbonylmethyl, isopropoxycarbonylmethyl,n-butyloxycarbonylmethyl, tert -butyloxycarbonylmethyl,1-methoxycarbonyloxy-ethyl, 1-ethoxycarbonyloxy-ethyl,1-propoxycarbonyloxy-ethyl, 1-isopropoxycarbonyloxyethyl,1-butyloxycarbonyloxy-ethyl and the like; alkoxycarbonylalkyl groupssuch as methoxycarbonylmethyl, ethoxycarbonylmethyl and the like;phthalidyl group; indanyl group; phenyl group; and phthalididenealkylgroups such as 2-(phthalidylidene)-ethyl,2-(5-fluorophthalidylidene)-ethyl, 2-(6-chlorophthalidylidene)ethyl,2-(6-methoxyphthalidylidene)-ethyl and the like.

R² represents a substituted or unsubstituted aryl, acylamino, aromaticheterocyclic, triazolyl or tetrazolyl group, said aromatic heterocyclicgroup being attached to the 3-exomethylene group through a carbon-carbonbond, and said triazolyl or tetrazolyl group being attached to the3-exomethylene group through a carbon-nitrogen bond. Herein, saidacylamino group is represented by the formula, R⁹ CONH-, wherein R⁹ is,for example, an alkyl, alkenyl, alkadienyl, cycloalkyl, cycloalkenyl,cycloalkadienyl, aryl, aralkyl, heterocyclic or heterocycle-alkyl group.Said aromatic heterocyclic group includes, for example, furyl, thienyl,pyridyl, benzofuryl, benzothienyl, quinolyl, isoquinolyl and the like.Said triazolyl or tetrazolyl group includes 1,2,3-triazolyl,1,2,4-triazolyl and 1,2,3,4-tetrazolyl. Though these triazolyl andtetrazolyl groups have isomers, any nitrogen atom in their ring may beattached to the 3-exomethylene. All the cases are included in thisinvention. Specific examples thereof are 1-(1,2,3-triazolyl),2-(1,2,3-triazolyl), 1-(1,2,4-triazolyl), 2-(1,2,4-triazolyl),4-(1,2,4-triazolyl), 1-(1,2,3,4-tetrazolyl) and 2-(1,2,3,4-tetrazolyl).

Further, the aryl, acylamino, aromatic heterocyclic, triazolyl andtetrazolyl groups for R² may be substituted by at least one substituentsuch as halogen, alkyl, aralkyl, aryl, alkenyl, hydroxyl, oxo, alkoxy,alkylthio, nitro, cyano, amino, alkylamino, dialkylamino, acylamino,acyl, acyloxy, acylalkyl, carboxyl, alkoxycarbonyl, carbamoyl,aminoalkyl, N-alkylaminoalkyl, N,N-dialkylaminoalkyl, hydroxyalkyl,hydroxyiminoalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl,aralkoxycarbonylalkyl, sulfoalkyl, sulfo, sulfamoyalkyl, sulfamoyl,carbamoylalkyl, carbamoyalkenyl, N-hydroxycarbamoylalkyl, and the like.Among these substituents, hydroxyl, amino and carboxyl may be protectedby an appropriate protecting group conventionally used in this field. Asthe protecting group for the hydroxyl group, there may be used allgroups which can conventionally be used for the protection of hydroxylgroup, specficially including readily removable acyl groups such asbenzyloxycarbony, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenzylocycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,4-(phenylazo)benzyloxycarbonyl, 4-(4-methoxyphenylazo)benzyloxycarbonyl,tert.-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl,diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,2,2,2-tribromoethoxycarbonyl, 2-furfuryloxycarbonyl,1-adamantyloxycarbonyl, 1-cyclopropylethoxycarbonyl,3-quinolyloxycarbonyl, acetyl, trifluoroacetyl and the like, as well asbenzyl, trityl, methoxymethyl, 2-nitrophenylthio, 2,4-dinitrophenylthioand the like. As the protecting group for the amino group, there may beused all groups which can conventionally be used for the protection ofamino group, specifically including readily removable acyl groups suchas trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl,p-toluenesulfonyl, p-nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl,o-nitrophenylsulfenyl, (mono-, di- or tri-)chloroacetyl,trifluoroacetyl, formyl, tert.-amyloxycarbonyl, tert.-butoxycarbonyl,p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,4-(phenylazo)benzyloxycarbonyl, 4-(4-methoxyphenylazo)benzyloxycarbonyl,pyridine-1-oxide-2-yl-methoxycarbonyl, 2-furyloxycarbonyl,diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl,isopropoxycarbonyl, 1-cyclopropylethoxycarbonyl, phthaloyl, succinyl,1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl and the like, as well assuch readily removable groups as trityl, 2-nitrophenylthio,2,4-dinitrophenylthio, 2-hydroxybenzylidene, 2-hydroxy5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene,3-hydroxy-4-pyridylmethylene, 1-methoxycarbonyl-2-propylidene,1-ethoxycarbonyl-2-propylidene, 3-ethoxycarbonyl-2-butylidene,1-acetyl2-propylidene, 1-benzoyl-2-propylidene,1-[N-(2-methoxyphenyl)carbamoyl]-2-propylidene,1-[N-(4-methoxyphenyl)carbamoyl]-2-propylidene,2-ethoxycarbonylcylcohexylidene, 2-ethoxycarbonylcyclopentylidene,2-acetylcyclohexylidene, 3,3-dimethyl-5-oxocyclohexylidene and the like,and other protecting groups for amino group such as di- ortri-alkylsilyl and the like. As the protecting group for carboxyl group,there may be used all groups which can conventionally be used for theprotection of carboxyl group, specifically including such groups asmethyl, ethyl, n-propyl, iso-propyl, tert,-butyl, n-butyl, benzyl,diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl, benzoylmethyl,acetylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl,p-methanesulfonylbenzoylmethyl, phthalimidomethyl, trichloroethyl,1,1-dimethyl-2-propenyl, 1,1-dimethylpropyl, acetoxymethyl,propionyloxymethyl, pivaloyloxymethyl, 3-metyl-3-butinyl,succinimidomethyl, 1-cyclopropylethyl, methylsulfenylmethyl,phenylthiomethyl, dimethylaminomethyl, quinoline1-oxide-2-yl-methyl,pyridine-1-oxide-2-yl-methyl, bis(p-methoxyphenyl)methyl and the like;non-metallic compounds such as titanium tetrachloride; and silylcompounds such as dimethylchlorosilane as mentioned in Japanese PatentApplication Kokai (Laid-Open) No. 7,073/71, and Dutch Patent ApplicationNo. 71 05259 (Laid-open).

In the formula [I], R⁴ represents a hydrogen atom or an amino groupwhich may be protected or substituted. As the protecting group for theamino group, there may be used groups which can conventionally be usedin the fields of penicillin and cephalosporin, specifically includingthe protecting groups for amino group mentioned as to R². As thesubstituent for said substituted amino group, there may be used, forexample, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heterocyclic, andheterocycle-alkyl groups. The amino group may be substituted by one ormore of these substitutents. These protecting groups and substituentsmay additionally be substituted by one or more substituents such ashalogen, alkyl, nitro, hydroxyl, alkoxy, oxo, thioxo, alkylthio,acylamino, acyl, acyloxy, aryloxy, carboxyl, carbamoyl, hydroxyalkyl,alkoxyalkyl, carboxyalkyl, alkoxycarbonyl, amino, alkylamino,aminoalkyl, N-alkylaminoalkyl, sulfoalkyl, sulfo, sulfamoyl,carbamoylalkyl, aryl, and heterocyclic groups, examples of theheterocyclic group being furyl, thienyl and the like. The hdyroxyl,amino and carboxyl groups used as the substituent may additionally beprotected with an appropriate protecting group which is conventionallyemployed, including, for example, the protecting groups for hydroxyl,amino and carboxyl groups mentioned as to R².

A represents --CH₂ -- or ##STR9## wherein R⁵ represents a hydrogen atomor an alkyl group The oxime compound wherein A represents ##STR10##covers it syn and anti isomers, as well as their mixtures.

In the group, ##STR11## of the formula [I], there exist tautomers whenR⁴ is an amino group which may be a protected or substitued amino group,as shown by the following equilibrium equation, and the tautomers arealso included in this invention: ##STR12## wherein R³ and R⁴ are asdefined above, and R^(4') represents an imino group which may beprotected or substituted. As the protecting group for imino grouprepresented by R^(4') in the above-mentioned equilibrium equation, theremay be amployed the groups conventionally used in the fields ofpenicillin and cephalosporin, specifically including the same groups asthe monovalent groups among the protecting groups for amino groupmentioned as to R².

As the substituent for said substituted imino group, there may be usedthe substituents for amino group mentioned as to R⁴.

As the salts of the compound represented by the formula [I], there maybe mentioned salts at the basic group or the acidic group usually knownin the fields of penicillin and cephalosporin, specifically includingsalts with mineral acids such as hydrochloric acid, nitric acid,sulfuric acid and the like; salts with organic carboxylic acids such asoxalic acid, succinic acid, formic acid, trichloroacetic acid,trifluoroacetic acid and the like; and salts with sulfonic acids such asmethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,toluene-2-sulfonic acid, toluene-4-sulfonic acid, mesitylenesulfonicacid (2,4,6-trimethylbenzenesulfonic acid), naphthalene-1-sulfonic acid,naphthalene-2 sulfonic acid, phenylmethanesulfonic acid,benzene-1,3-disulfonic acid, toluene-3,5-disulfonic acid,naphthalene-1,5-disulfonic acid, naphthalene-2,6-disulfonic acid,naphthalene-2,7-disulfonic acid, benzene-1,3,5-trisulfonic acid,benzene-1,2,4-trisulfonic acid, naphthalene-1,3,5-trisulfonic acid andthe like (as the salts at the basic group), and salts with alkali metalssuch as sodium, potassium and the like; salts with alkaline earth metalssuch as calcium, magnesium and the like; ammonium salts; salts withnitrogen-containing organic bases such as procaine, dibenzylamine,N-benzyl-β-phenethylamine, 1-ephenamine, N,N-dibenzylethylenediamine,triethylamine, trimethylamine, tributylamine, pyridine, dimethylaniline,N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamineand the like (as the salts at the acidic group).

Further, this invention covers all the optical isomers, racemiccompounds, and all crystal forms and hydrates of the compoundsrepresented by the formula [I] and their salts.

Among the compounds of this invention represented by the formula [I],preferred are those in which A is a group represented by ##STR13## amongwhich those in which R⁵ is a hydrogen atom or a methyl group are morepreferable. When R⁵ is a methyl group, syn isomers are particularlypreferable. Other examples of preferable compounds are those in which R²is a substituted or unsubstituted triazolyl or tetrazolyl group attachedto the exomethylene group at the 3-position of the cephem ring, amongwhich those in which R² is a substituted or unsubstituted1,2,4-triazolyl or 2-(1,2,3,4-tetrazolyl) group are particularlypreferable.

The results of a test for the pharmacological effect of the typicalcompounds of this invention are as follows:

(1) Antibacterial activity

According to the standard method of the Japanese ChemotherapeuticSociety [Chemotherapy, Vol. 23, Pages 1-2 (1975)], a culture obtained bycultivating bacteria in Heart Infusion broth (manufactured by EikenKagakusha) at 37° C. for 20 hours was inoculated into a Heart Infusionagar medium (manufactured by Eiken Kagakusha) and cultivated at 37° C.for 20 hours, after which the growth of bacteria was examined visually.The minimum inhibitory concentration at which the bacterial growth wasinhibited was taken as MIC (μg/ml). The amount of the inoculatedbacteria was 10⁴ cells/plate (10⁶ cells/ml).

Test compounds:

(A) Trifluoroacetic acid salt of7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[(3-acetamido-1,2,4-triazolyl)methyl]-Δ³-cephem-4-carboxylic acid*,

(B) Trifluoroacetic acid salt of7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-(furan-2-yl-carboxamido)methyl-Δ³-cephem-4-carboxylic acid,

(C) Trifluoroacetic acid salt of7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-acetamidomethyl-Δ³-cephem-4-carboxylic acid,

(D) Trifluoroacetic acid salt of7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-(4-hydroxybenzyl)-Δ³-cephem-4-carboxylic acid,

(E) Trifluoroacetic acid salt of7-[2-(2-aminothiazol-4-yl)-2-(syn)-hydroxyiminoacetamido]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-A3-cephem-4-carboxylicacid,

(F) Trifluoroacetic acid salt of7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[2-(1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylic acid,

(G) Trifluoroacetic acid salt of7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[1-(1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylic acid,

(H) Trifluoroacetic acid salt of7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[2-(5-amino-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylic acid,

(I) Trifluoroacetic acid salt of7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[2-(5-acetamido-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylic acid,

(J) Trifluoroacetic acid salt of7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylic acid,

(K) Trifluoroacetic acid salt of7-L2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[2-(5-ethyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylic acid,

(L) Trifluoroacetic acid salt of7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[(3-chloro-1,2,4-triazolyl)methyl]-Δ³-cephem-4-carboxylic acid*,

(M) Trifluoroacetic acid salt of7-[2-(2-aminothiazol-4-yl)acetamido]-3-[2-(5-acetamido-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylic acid, and

(N) Trifluoroacetic acid salt of7-[2-(2-aminothiazol-4-yl)acetamido]-3-[2-(1,2,3,4-tetrazolyl)methyl]-.DELTA.³-cephem-4-carboxylic acid

                                      TABLE 1                                     __________________________________________________________________________             Antibacterial Activity                                                        MIC (μg/ml)                                                       __________________________________________________________________________                Compound                                                          Bacteria    Cephazoline                                                                          A   B   C   D   E   F   G                                  __________________________________________________________________________    E. coli NIHJ                                                                              1.56   ≦0.1                                                                       ≦0.1                                                                       ≦0.1                                                                       ≦0.1                                                                       ≦0.1                                                                       ≦0.1                                                                       ≦0.1                        E. coli TK3 25     0.39                                                                              0.39                                                                              0.39                                                                              1.56                                                                              0.78                                                                              ≦0.1                                                                       0.39                               (Penicillinase-                                                               producing bacteria)                                                           Kl. pneumoniae Y-50                                                                       1.56   ≦0.1                                                                       ≦0.1                                                                       ≦0.1                                                                       0.2 ≦0.1                                                                       ≦0.1                                                                       ≦0.1                        Klebsiella spp Y-72                                                                       >200   6.25                                                                              1.56                                                                              6.25                                                                              6.25                                                                              3.13                                                                              --  --                                 Kl. pneumoniae Y-41                                                                       3.13   0.2 0.2 0.2 0.78                                                                              0.2 ≦0.1                                                                       0.2                                Ent. cloacae IID977                                                                       >200   6.25                                                                              25  50  25  6.25                                                                              12.5                                                                              6.25                               Ser. marcescens IID620                                                                    >200   0.78                                                                              0.2 1.56                                                                              3.13                                                                              3.13                                                                              0.39                                                                              1.56                               Pro. morganii T-216                                                                       >200   0.2 0.39                                                                              0.78                                                                              0.78                                                                              ≦0.1                                                                       ≦0.1                                                                       0.2                                Pro. mirabilis T-111                                                                      6.25   0.2 0.2 0.39                                                                              0.78                                                                              0.39                                                                              ≦0.1                                                                       0.2                                Pro. mirabilis T-100                                                                      --     ≦0.1                                                                       ≦0.1                                                                       ≦0.1                                                                       ≦0.1                                                                       ≦0.1                                                                       --  --                                 Pro. vulgaris GN76                                                                        >200   3.13                                                                              0.78                                                                              6.25                                                                              1.56                                                                              6.25                                                                              0.78                                                                              0.78                               (Cephalosporinase-                                                            producing bacteria)                                                           Al. faecalis B-1                                                                          100    50  12.5                                                                              12.5                                                                              25  3.13                                                                              3.13                                                                              12.5                               Aci. calcoaceticus A-6                                                                    200    25  25  12.5                                                                              6.25                                                                              50  6.25                                                                              25                                 __________________________________________________________________________                         Compound                                                          Bacteria    H   I   J   K   L   M  N                                 __________________________________________________________________________             E. coli NIHJ                                                                              ≦0.1                                                                       ≦0.1                                                                       ≦0.1                                                                       ≦0.1                                                                       ≦0.1                                                                       0.39                                                                             0.39                                       E. coli TK3 0.78                                                                              0.39                                                                              0.39                                                                              0.39                                                                              0.39                                                                              1.56                                                                             1.56                                       (Penicillinase-                                                               producing bacteria)                                                           Kl. pneumoniae Y-50                                                                       0.2 ≦0.1                                                                       ≦0.1                                                                       0.2 ≦0.1                                                                       0.78                                                                             0.39                                       Klebsiella spp Y-72                                                                       --  --  --  --  --  -- --                                         Kl. pneumoniae Y-41                                                                       0.39                                                                              0.2 ≦0.39                                                                      0.78                                                                              0.39                                                                              0.78                                                                             0.78                                       Ent. cloacae IID977                                                                       12.5                                                                              --  --  --  --  -- --                                          Ser. marcescens IID620                                                                   0.78                                                                              --  --  --  --  -- --                                         Pro. morganii T-216                                                                       0.78                                                                              --  --  --  --  -- --                                         Pro. mirabilis T-111                                                                      0.39                                                                              ≦0.1                                                                       0.2 0.78                                                                              0.78                                                                              0.78                                                                             0.78                                       Pro. mirabilis T-100                                                                      --  ≦0.1                                                                       ≦0.1                                                                       ≦0.1                                                                       ≦0.1                                                                       0.39                                                                             0.39                                       Pro. vulgaris GN76                                                                        1.56                                                                              --  --  --  --  -- --                                         (Cephalosporinase-                                                            producing bacteria)                                                           Al. faecalis B-1                                                                          12.5                                                                              --  --  --  --  -- --                                         Aci. calcoaceticus A-6                                                                    25  --  --  --  --  -- --                                __________________________________________________________________________

(2) Oral administration experiment

Each test compound was administered orally to mice (ICR, male, 4 weeksold) at a dose of 2 mg per head, and the recovery of the compound fromurine was determined. The results are shown in Table 2. After beingabsorbed in living body, all the test compounds were readily freed fromthe ester group to give the corresponding free carboxylic acids.Therefore, the free carboxylic acid excreted into urine wasquantitatively analyzed and taken as recovery from urine.

Method of administration:

The test compound was suspended in 0.5% CMC solution and then orallyadministered.

Method of quantitative analysis:

The quantitative analysis were carried out by a paper disc method withthe testing bacteria mentioned in Table 2.

                                      TABLE 2                                     __________________________________________________________________________     ##STR14##                                                                    Compound                   Recovery from                                                                         Testing                                    A      R.sup.1    R.sup.2  urine (%)*                                                                            bacteria                                   __________________________________________________________________________    CH.sub.2                                                                             CH.sub.2 OCOC(CH.sub.3).sub.3                                                             ##STR15##                                                                             45.1    M. luteus ATCC9341                         CH.sub.2                                                                             "                                                                                         ##STR16##                                                                             32.0    M. luteus ATCC9341                          ##STR17##                                                                           "          "        33.1    M. luteus ATCC9341                                 ##STR18## "        35.0    M. luteus ATCC9341                          ##STR19##                                                                           CH.sub.2 OCOC(CH.sub.3).sub.3                                                             ##STR20##                                                                             47.0    Kl. pneumoniae ATCC10031                    ##STR21##                                                                           "                                                                                         ##STR22##                                                                             28.8    M. luteus ATCC9341                         __________________________________________________________________________     Note:-                                                                        *0-4 hrs.; average value of 5 cases.                                     

(3) Acute toxicity test

Three test compounds were introvenously administered to mice (ICR, male,4 weeks old) to test their acute toxicities. The results are as shown inTable 3.

                                      TABLE 3                                     __________________________________________________________________________                                      LD.sub.50                                   Test Compound                     (g/kg)                                      __________________________________________________________________________     ##STR23##                        >3.0                                         ##STR24##                        >3.0                                         ##STR25##                        >3.0                                        __________________________________________________________________________

The compounds represented by the formula [I] and their salts can beadministered to human and animals in the form of free acid, non-toxicsalt or physiologically acceptable ester for the purpose of treating andpreventing bacterial infectious diseases. It is preferred that thecompounds be parenterally administered in the form of free acid ornon-toxic salt or orallyl administered in the form of physiologicallyacceptable ester. In these cases, they may be prepared into preparationforms which are conventionally applied to cephalosporin drugs, such astablet, capsule, powder, granule, fine granule, syrup, injection(including drop), suppository and the like. In producing theabove-mentioned drugs, there may, if necessary, be used diluents and/oradditives including excipients such as starch, lactose, sucrose, calciumphosphate, calcium carbonate and the like, binders such as gum arabic,starch, crystalline cellulose, carboxymethyl cellulose, hydroxypropylcellulose and the like, lubricants such as talc, magnesium stearate andthe like, and disintegrators such as carboxymethyl calcium, talc and thelike.

In administering the cephalosporin preparation of this invention tohuman, the dose and the number of repetitions of administration areappropriately selected depending on the condition-of illness and others.It is usual, however, to administer the preparation either orally orparenterally at a dose of about 50-5,000 mg of the ecephalosporincompound of this invention at 1-4 times a day, per adult.

This invention provides not only the compounds represented by theformula [I] and salts thereof mentioned hereinbefore and processes forproducing the same, which processes will be mentioned below, but alsointermediates represented by the formulas [IIIb], [IV] and [V] and saltsthereof which will be described below and a process for producing anintermediate represented by the formula [IIIa] and salts thereof, whichprocess will be described hereinafter. ##STR26## wherein R¹, R², R³, R⁴,A and B are as defined above; R^(2a) represents a substituted orunsubstituted triazolyl or tetrazolyl group attached to the exomethylenegroup at the 3-position of the cephem ring through a carbon-nitrogenbond as explained as to R² ; R^(2b) represents a substituted orunsubstituted 1,2,4-triazolyl or 2-(1,2,3,4-tetrazolyl)group; R¹⁶represents a halogen atom; and R¹⁰ is as defined below.

An explanation is made below of the process for producing thesecompounds of this invention. That is, these compounds can be produced,for example, by the reaction route shown below.

Though the intermediate of this invention and its salt have per se anantibacterial activity, they are useful compounds convertible to thenovel cephalosporins represented by the formula [I], as can beunderstood from the reaction routes shown below. ##STR27## wherein R¹,R², R³, R⁴, R⁵, A, B and the bond are as defined above; B¹ representsthe lower alkoxy group mentioned as to B; Y represents --S--, or##STR28## M¹ represents an alkali metal atom or an alkaline earth metalatom; m¹ represents an integer of 1 or 2; R¹⁰ represents an amino group,a group of the formula, ##STR29## in which R¹¹, R¹² and R¹³, which maybe identical or different, represent hydrogen atoms or organic residuesnot participating in the reaction, or a group of the formula, ##STR30##in which R¹⁴ and R¹⁵, which may be identical or different, representshydrogen atoms or organic residues not participating in the reaction;and R¹⁷ represents a substituted or unsubstituted acyloxy orcarbamoyloxy group.

In the compounds represented by the formulas [II] and [III] and theirsalts, R¹⁰ includes an amino group, a group represented by the formula,##STR31## and a group represented by the formula, ##STR32## and thegroup represented by the formula, ##STR33## means to include a grouprepresented by the formula, ##STR34## which is an isomer of the former.

As the organic residue not participating in the reaction at R¹¹, R¹²,R¹³, R¹⁴ and R¹⁵ in the above-mentioned formulas, there may be usedsubstituted or unsubstituted aliphatic, alicyclic, aromatic,ar-aliphatic, heterocyclic, and acyl residues, and the following groupsmay specifically be mentioned:

(1) Aliphatic residues: for example, alkyl groups and alkenyl groups,

(2) Alicyclic residues: for example, cycloalkyl groups and cycloalkenylgroups,

(3) Aromatic residues: for example, aryl groups,

(4) Ar-aliphatic residues: for example, aralkyl groups,

(5) Heterocyclic residues: for example, heterocyclic groups,

(6) Acyl groups: acyl groups which can be derived from organiccarboxylic acids, and examples of said organic carboxylic acids arealiphatic carboxylic acids; alicyclic carboxylic acids;alicycloaliphatic carboxylic acids; aromatic-substituted aliphaticcarboxylic acids; aromatic-oxyaliphatic carboxylic acids;aromatic-thioaliphatic carboxylic acids; heterocycle-substitutedaliphatic carboxylic acids; heterocyclic-oxyaliphatic carboxylic acids;or heterocyclic-thioaliphatic carboxylic acids; organic carboxylic acidsin which an aromatic ring, aliphatic group or alicylic group is attachedto the carbonyl group through an oxygen, nitrogen or sulfur atom;aromatic carboxylic acids; heterocyclic carboxylic acids; and the like.

As said aliphatic carboxylic acids, there may be mentioned formic acid,acetic acid, propionic acid, butanoic acid, isobutanoic acid, pentanoicacid, methoxyacetic acid, methylthioacetic acid, acrylic acid, crotonicacid and the like; and as said alicyclic carboxylic acids, there may bementioned cyclohexanoic acid and the like; and as said alicycloaliphaticcarboxylic acids, there may be mentioned cyclopentane-acetic acid,cyclohexane-acetic acid, cyclohexanepropionic acid,cyclohexadiene-acetic acid and the like.

As the aromatic residue in the above-mentioned organic carboxylic acids,the aryl groups mentioned hereinbefore as examples can be used; and assaid heterocyclic ring, there may be used the heterocyclic groupsmentioned hereinbefore as examples.

Further, the individual groups constituting these organic carboxylicacids may additionally be substituted by a substituent such as halogen,hydroxyl, protected hydroxyl, alkyl, alkoxy, acyl, nitro, amino,protected amino, carboxyl, protected carboxyl, or the like.

As said protecting group for amino, hydroxyl and carboxyl groups, theprotecting groups mentioned as to R² may be used.

The derivatives of the compound of the formula [II] at its carboxylgroup include, for example, the followings:

(a) Esters: Esters conventionally used in the fields of penicillin andcephalosporin may be used, and include specifically the esters mentionedas to R¹.

(b) Anhydrides of the carboxyl group with N-hydroxysuccinimide,N-hydroxyphthalimide, dimethylhydroxylamine, diethylhydroxylamine,1-hydroxypiperidine, oxime and the like.

(c) Amides: Acid amides, N-substituted acid amides and N,N-disubstitutedacid amides are all included, and there may specifically be mentionedN-alkyl acid amides such as N-methyl acid amide, N-ethyl acid amide andthe like; N-aryl acid amides such as N-phenyl acid amide and the like;N,N-dialkyl acid amides such as N,N-dimethyl acid amide, N,N-diethylacid amide, N-ethyl-N-methyl acid amide and the like; and acid amideswith imidazole, 4-substituted imidazole, triazolopyridone and the like.

As the acyloxy and carbamoyloxy groups for R¹⁷, there may specificallybe mentioned alkanoyloxy groups such as acetoxy, propionyloxy,butyryloxy and the like; alkenoyloxy groups such as acryloyloxy and thelike; aroyloxy groups such as benzoyloxy, naphthoxyloxy and the like;and carbamoyloxy group. They may be substituted by one or moresubstituents such as halogen, nitro, alkyl, alkoxy, alkylthio, acyloxy,acylamino, hydroxyl, carboxyl, sulfamoyl, carbamoyl,carboalkoxycarbamoyl, aroylcarbamoyl, carboalkoxysulfamoyl, aryl,carbamoyloxy, and the like.

In the above-mentioned substituents on R¹⁷, the hydroxyl, amino, andcarboxyl groups may be protected with conventional protecting groups. Asthe protecting group, there may be used the protecting groups forhydroxyl, amino and carboxyl groups mentioned as to R².

The salts referred to in the above-mentioned reaction route diagraminclude both of the salts at acidic group and the salts at basic group,and specifically, the salts mentioned as to the compound represented bythe formula [I] may be used.

This invention also covers all the isomers of the intermediates (forexample, syn and anti isomers, tautomers, optical isomers and the like),as well as their mixtures, all crystalline forms and hydrates.

Further, an explanation is made of the process for producing thecompounds represented by the formulas [I] (including [Ia], [Ib], [Ic],[Id] and [Ie]), [III] (including [IIIa] and [IIIb]), [IV] (including[IVa]), [V], [VIII] and [X] and their salts. The reaction routes toproduce these compounds are as shown in the above reaction routediagram.

(1) In the conversion reaction at 3-position of route 1, 7-substitutedor unsubstituted amino-3-substituted methyl-Δ³ -cephem-4-carboxylicacids represented by the formula [III] (including [IIIa] and [IIIb],too; hereinafter the same applies) or their salts can be produced byreacting the cephalosporanic acid represented by the formula [II] or itsderivative in the carboxyl group or a salt thereof with a substituted orunsubstituted aromatic hydrocarbon, a substituted or unsubstitutednitrile compound, a substituted or unsubstituted aromatic heretocycliccompound or triazole or tetrazole, which may have substituents on thecarbon atoms in the ring, in an organic solvent in the presence of anacid or an acid complex compound and subsequently, if desired, removingthe protecting group, protecting the carboxyl group or converting thecarboxyl group to a salt. Further, if necessary, the substituent on the7-amino group may be removed by a conventional method to give a7-unsubstituted amino compound.

According to this production process, the compound represented by theformula [II], its derivative in the carboxyl group or a salt thereof maybe reacted with a substituted or unsubstituted aromatic hydrocarbon toobtain a compound of the formula [III] or its salt in which R² is thecorresponding aromatic hydrocarbon group, or similarly, reacted with asubstituted or unsubstituted nitrile compound to obtain a compound ofthe formula [III] or its salt in which R² is the corresponding acylaminogroup, or similarly, reacted with a substituted or unsubstitutedaromatic heterocyclic compound to obtain a compound of the formula [III]or its salt in which R² is the corresponding aromatic heterocyclicgroup, or similarly, reacted with triazole or tetrazole, which may havesubstituents on the carbon atoms in the ring to obtain a compound of theformula [III] or its salt in which R² is the corresponding substitutedor unsubstituted triazolyl or tetrazolyl group (namely, a compound ofthe formula [IIIa] or its salt). In all the above cases, the reaction isconducted by an industrially easy operation to obtain the product in ahigh yield with a high purity.

As the substituted or unsubstituted aromatic hydrocarbon which is thereactant in said reaction, there may be used an aromatic hydrocarboncorresponding to the substituted or unsubstituted aromatic hydrocarbongroup for R², namely an aromatic hydrocarbon represented by R² H (R²means the substituted or unsubstituted aromatic hydrocarbon groupmentioned above as to R²). As said substituted or unsubstituted nitrilecompound, there may similarly be used a nitrile compound correspondingto the substituted or unsubstituted acylamino group for R², namely anitrile compound represented by R⁹ CN (R⁹ is as defined above). As thesubstituted or unsubstituted aromatic heterocyclic compound, there maybe similarly used an aromatic heterocyclic compound corresponding to thesubstituted or unsubstituted aromatic heterocyclic group for R², namelyan aromatic heterocyclic compound represented by R² H (R² means thesubstituted or unsubstituted aromatic heterocyclic group mentioned aboveas to R²). As the triazole or tetrazole which may have substitutens onthe carbon atoms in the ring, there may similarly be used a triazole ortetrazole corresponding to the substituted or unsubstituted triazolyl ortetrazolyl group for R², namely a triazole or tetrazole represented byR² H (R² means the substituted or unsubstituted triazolyl or tetrazolylgroup mentioned above as to R²).

In these triazoles and tetrazoles, tautomers exist as shown below. Anyof these isomers and any of their mixtures may be used in the reaction.##STR35## wherein R represents a hydrogen atom or the substituentsmentioned above at to R², and the two R's may be identical or different.

The triazoles and tetrazoles which may have substituents on the carbonatoms in the ring may, if necessary, be used in the form of a basic saltor an acidic salt for the reaction. As said basic salt and acidic salt,there may be used the same salt forms as the salts in the carboxyl groupand amino group mentioned as to the salt of the compound represented bythe formula [I]. The salt of the compound represented by the formula[II] may previously be isolated and then used, or may be prepared insitu.

As the acid or acid complex compound used in the above reaction,probonic acids, Lewis acids and complex compounds of Lewis acids may beused. As the protonic acid, there may be mentioned sulfuric acids,sulfonic acids and super-acids (the term "super-acids" means acidsstronger than 100% sulfuric acid and includes some of theabove-mentioned sulfuric acids and sulfonic acids). Specifically, theremay be used sulfuric acid, chlorosulfuric acid, fluorosulfuric acid andthe like as the sulfuric acids; alkyl(mono- or di-)sulfonic acids, forexample, methanesulfonic acid, trifluoromethanesulfonic acid and thelike and aryl(mono-, di- or tri-)sulfonic acids, for example,p-toluenesulfonic acid and the like as the sulfonic acids; andperchloric acid, magic acid (FSO₃ H-SbF₃), FSO₃ H-AsF₅, CF₃ SO₃ H-SbF₅,HF-BF₃, H₂ SO₄ -SO₃ and the like as the super-acids. As the Lewis acids,boron trifluoride may be mentioned as an example. As the complexcompound of Lewis acid, there may be mentioned complex salts of borontrifluoride with dialkyl ethers such as diethyl ether, di-n-propylether, di-n-butyl ether and the like; complex salts of boron trifluoridewith amines such as ethylamine, n-propylamine, n-butylamine,triethanolamine and the like; complex salts of boron trifluoride withcarboxylic esters such as ethyl formate, ethyl acetate and the like;complex salts of boron trifluoride with aliphatic acids such as aceticacid, propionic acid and the like; complex salts of boron trifluoridewith nitriles such as acetonitrile, propionitrile and the like.

As the organic solvent in this reaction, all the organic solvents whichdo not adversely affect the reaction may be used, and there mayspecifically be mentioned nitroalkanes such as nitromethane,nitroethane, nitropropane and the like; organic carboxylic acids such asformic acid, acetic acid, trifluoroacetic acid, dichloroacetic acid,propionic acid and the like; ketones such as acetone, methyl ethylketote, methyl isobutyl ketone and the like; ethers such as diethylether, diisopropyl ether, dioxane, tetrahydrofuran, ethylene glycoldimethyl ether, anisole and the like; esters such as ethyl formate,diethyl carbonate, methyl acetate, ethyl acetate, ethyl chloroacetate,butyl acetate and the like; nitriles such as acetonitrile, butyronitrileand the like; and sulfolanes such as sulfolane and the like. Thesesolvents may be used alone or in admixture of two or more. Furthermore,complex compounds formed from these organic solvents and Lewis acids mayalso be used as the solvent. The amount of the acid or complex compoundof acid used is 1 mole or more per mole of the compound represented bythe formula [II] or its derivative in the carboxyl group or the saltthereof, and may be varied depending upon the conditions. It isparticularly preferable to use the acid or complex compound of acid inan amount of 2-10 moles per mole of the latter. When the complexcompound of acid is used, it may per se be used as a solvent or amixture of two or more complex compounds may be used.

The amount of the aromatic hydrocarbon, nitrile compound, aromaticheterocyclic compound or triazole or tetrazole used as a reactant forthe above reaction is 1 mole or more per mole of the compoundrepresented by the formula [II] or its derivative in the carboxyl groupor the salt thereof. It is particularly preferable to use them in anamount of 1.0-5.0 moles per mole of the latter.

This reaction is usually carried out at a temperature of 0°-80° C., andthe reaction time is generally several minutes to tens of hours. Ifwater exists in the system of this reaction, there is a fear thatundesirable side reactions such as lactonization of the startingcompound or product and cleavege of the β-lactam ring be caused.Therefore, the reaction system is preferably kept in an anhydrous state.In order to fulfil this requirement, to the reaction system may be addedan appropriate dehydrating agent such as a phosphorus compound (forexample, phosphorus pentoxide, polyphosphoric acid, phosphoruspentachloride, phosphorus trichloride, phosphorus oxychloride or thelike), an organic silylating agent (for example,N,O-bis(trimethylsilyl)acetamide, trimethylsilylacetamide,trimethylchlorosilane, dimethyldichlorosilane or the like), an organicacid chloride (for example, acetyl chloride, p-toluenesulfonyl chlorideor the like), an acid anhydride (for example, acetic anhydride,trifluoroacetic anhydride or the like), an inorganic drying agent (forexample, anhydrous magnesium sulfate, anhydrous calcium chloride,molecular sieve, calcium carbide or the like), or the like.

If a derivative in the carboxyl group of the compound of the formula[II] is used as the starting compound in the above reaction, there can,in some cases, be obtained, depending on the treatment after thereaction, the corresponding compound of the formula [III] having a freecarboxyl group at the 4-position of the cephem ring. However, thecorresponding compound of the formula [III] having a free carboxyl groupat the 4-position can also be obtained by effecting the removal reactionin the conventional manner.

When a compound of the formula [III] in which R¹ is a hydrogen atom isobtained in this reaction, it can be esterified or converted to a saltin the conventional manner. When a compound of the formula [III] inwhich R¹ is an ester group is obtained, it can be subjected to removalreaction in the conventional manner to obtain a compound of the formula[III] in which R¹ is a hydrogen atom, which can subsequently beconverted to a salt or other ester optionally. When a compound of theformula [III] in which R¹ is a salt-forming group is obtained, it can besubjected to a desalting reaction in the conventional manner to obtain acompound of the formula [III] in which R¹ is a hydrogen atom and furtherto that in which R¹ is an ester group, optionally.

When the substituent attached to the aromatic hydrocarbon, nitrilecompound, aromatic heterocyclic compound or the carbon atom in the ringof the triazole or tetrazole which are reactants of the above reactionis substituted by hydroxyl, amino, or carboxyl, the desired compound canbe obtained by first protecting these groups with the aforementionedprotecting group before carrying out the reaction and subjecting it,after completion of the reaction, to the conventional removal reaction.

When a compound of the formula [III] in which R² is a substituted orunsubstituted aryl group or an aromatic heterocyclic group attached tothe exomethylene group at the 3-position of the cephem ring through acarbon-carbon bond is obtained, there may be applied, in addition to theabove-mentioned 3-position conversion reaction, a known method by whicha penicillin as the starting material is subjected to the opening of thethiazolidine ring, then to the reaction with 3-R² -prop-2-ynyl bromideto open the ring and thereafter to a series of reactions for forming adihydrothiadine ring (namely the cephalosporin skeleton) (see JapanesePatent Application Kokai (Laid-Open) No. 5,393/75; J.M.C., 20, 1082(1977); ibid., 20, 1086 (1977)).

When a compound of the formula [III] in which B is a hydrogen atom isobtained in the above reaction, it can be converted to a compound of theformula [III] in which B is a lower alkoxy group by loweralkoxylatingthe 7α-position of the formula [III] in a manner known in this field[the Journal of Synthetic Organic Chemistry, Japan, Vol. 35, 568-574(1977)].

(2) The acylating reactions of routes 1-4 can be carried out all insubstantially the same manner. In these acylating reactions, a compoundrepresented by the formula [III] or a salt thereof is reacted with acompound represented by the formula [VI], [VII], [IX], [XII] or [XIII]or a reactive derivative thereof to obtain a compound represented by theformula [I], [IV], [V], [VIII] or [X] or a salt thereof.

As the reactive derivatives of the compounds represented by the formulas[VI], [VII], [IX], [XII] and [XIII], there may specifically mentionedacid halides, acid anhydrides, mixed acid anhydrides, active acidamides, active esters and the reactive derivatives formed betweenVilsmeier reagent and the compound represented by the formula [VI],[VII], [IX], [XII] or [XIII]. As said mixed acid anhydride, there may beused mixed acid anhydrides with monoalkyl carbonates such as monoethylcarbonate, monoisobutyl carbonate and the like; and mixed acidanhydrides with lower alkanoic acids optionally substituted by halogensuch as pivalic acid, trichloroacetic acid and the like. As said activeacid amide, there may be used, for example, N-acylsaccharin,N-acylimidazole, N-acylbenzoylamide, N,N'-dicylcohexyl-N-acylurea,N-acylsulfonamide and the like. As said active ester, there may be used,for example, cyanomethyl esters, substituted phenyl esters, substitutedbenzyl esters, substituted thienyl esters and the like.

As said reactive derivative with Vilsmeier reagent, there may be usedthe reactive derivatives with a Vilsmeier reagent obtained by reactingan acid amide such as dimethylformamide, N,N-dimethylacetamide or thelike with a halogenating agent such as phosgene, thionyl chloride,phosphorus trihloride, phosphorus tribromide, phoshporus oxychloride,phosphorus oxybromide, phosphorus pentachloride, trichloromethylchloroformate, oxalyl chloride and the like.

When the compound of the formula [VI], [VII], [IX], [XII] or [XIII] isused in the state of a free acid or salt, an appropriate condensingagnet is used. As said condensing agent, there may be usedN,N'-disubstituted carbodiimides such as N,N'-dicyclohexylcarbodiimideand the like, azolide compound such as N,N'-thionyldiimidazole and thelike, dehydrating agents such asN-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline, phosphorusoxychloride, alkoxyacetylene and the like, 2-halogenopyridinium saltssuch as 2-chloropyridinium methyl iodide, 2-fluoropyridinium methyliodide and the like.

These acylating reactions are generally carried out in an appropriatesolvent in the presence or absence of a base. As said solvent, there areoften used halogenated hydrocarbons such as chloroform, methylenedichloride and the like, ethers such as tetrahydrofuran, dioxane and thelike, dimethylformamide, dimethylacetamide, acetone, water and mixturesthereof. The base used herein includes inorganic bases such as alkalihydroxides, alkali hydrogen carbonates, alkali carbonates, alkaliacetates and the like; tertiary amines such as trimethylamine,triethylamine, tributylamine, pyridine, N-methylpiperidine,N-methylmorpholine, lutidine, collidine and the like; and secondaryamines such as dicyclohexylamine, diethylamine and the like.

The amount of the compound represented by the formula [VI], [VII], [IX],[XII] or [XIII] or its reactive derivative used in the acylatingreactions of routes 1-4 is usually about 1 mole to several moles permole of the compound represented by the formula [III] or its salt. Thereaction is usually carried out at a temperature ranging from -50° C. to+40° C., and the reaction time is usually 10 minutes to 48 hours.

In the acylating reaction of route 3 wherein A is --CH₂ --, a compoundof the formula [XIII] wherein A is --CH₂ -- or its salt can also beobtained by reacting the diketene and halogen according to the method ofthe Journal of the Chemical Society, 97, 1987 (1910) and then reactingthe reaction product with a compound of the formula [III] or its salt.

When the compound obtained by the acylating reactions of routes 1-4 is acompound of the formula [I], [IV], [V], [VIII] or [X] wherein R¹ is acarboxylprotecting group, the compound can be converted in aconventional manner to the corresponding compound or its salt wherein R¹is hydrogen; and when it is a compound of the formula [I], [IV], [V],[VIII] or [X] wherein R^(l) is a hydrogen atom, the compound can beconverted in a conventional manner to the corresponding compound or itssalt wherein R¹ is a carboxyl-protecting group; and when it is a salt ofthe formula [I], [IV], [V], [VIII] or [X], the compound can be convertedin a conventional manner to the corresponding free compound.

When, in these acylating reactions, there is a group active to thereaction among the groups R¹, R² and R⁴, the active group may beprotected in any manner with a conventional protecting group at the timeof reaction, and the protecting group can be removed after the reactionin a conventional manner.

The compounds of the formulas [I], [IV], [V], [VIII] and [X] and theirsalts thus obtained can be isolated by a conventional method.

(3) When, in the compound represented by the formula [IV] or its saltobtained by the acylating reaction of route 3, A is --CH₂ --, it may besubjected to a nitroso-forming reaction mentioned hereinafter (andoptionally a subsequent alkylating reaction) to convert A into ##STR36##and thereafter to a subsequent ring closure reaction.

The nitroso-forming reaction can be carried out in the following manner:

The reaction of a compound represented by the formula [VIII] or its saltwith a nitroso-forming agent to convert it to a compound represented bythe formula [VII] or its salt is usually carried out in a solvent. Assaid solvent, there may be used solvents which do not adversely affectthe reaction such as water, acetic acid, benzene, methanol, ethanol,tetrahydrofuran and the like. The preferable examples of thenitroso-forming agent are nitric acid and its derivatives such asnitrosyl halides (for example, nitrosyl chloride, nitrosyl bromide andthe like), alkali metal nitrites (for example, sodium nitrite, potassiumnitrite and the like), alkyl nitrites (for example, butyl nitrite,pentyl nitrite and the like). When a salt of nitrous acid is used as thenitroso-forming agent, the reaction is preferably carried out in thepresence of an inorganic or organic acid such as hydrochloric acid,sulfuric acid, formic acid, acetic acid or the like. When an ester ofnitrous acid is used as the nitroso-forming agent, it is also possibleto carry out the reaction in the presence of a strong base such as analkali metal alkoxide. Though the reaction temperature is not critical,it is usually preferable to carry out the reaction with cooling or atroom temperature. Salts of the compounds represented by the formula [X]wherein R⁵ is a hydrogen atom can easily be obtained by a conventionalmethod. Said salts may be the same as mentioned as to the salts of thecompound of the formula [I]. The thus obtained compounds of the formula[X] wherein R⁵ is a hydrogen atom, as well as their salts, can beisolated and purified in the well known manner. It is also possible,however, to use them as the starting compound for the subsequentreaction without separating them.

(4) After the above-mentioned nitroso-forming reaction, the product issubjected to alkylating reaction in order to obtain a compound of theformula [X] wherein R⁵ is an alkyl group, and the alkylating reactioncan be carried out according to the usual method. For example, it can becompleted in several minutes to several hours in most cases if it iscarried out in a solvent with cooling or in the neighborhood of roomtemperature. As the solvent, any solvent may be used so far as it doesnot retard this reaction, and the solvents usable includetetrahydrofuran, dioxane, methanol, ethanol, chloroform, methylenedichloride, ethyl acetate, butyl acetate, N,N-dimethylformamide,N,N-dimethylacetamide, water and the like and mixtures thereof.

As the alkylating agent, for example, methyl iodide, methyl bromide,ethyl iodide, ethyl bromide, dimethyl sulfate, diethyl sulfate,diazomethane, diazoethane, methyl p-toluenesulfonate and the like areused. When the alkylating agents other than diazomethane and diazoethaneare used, the reaction is generally carried out in the presence of abase such as an alkali metal carbonate (for example, sodium carbonate,potassium carbonate or the like), an alkali metal hydroxide (forexample, sodium hydroxide, potassium hydroxide or the like),triethylamine, pyridine, dimethylaniline or the like.

Salts of the compound represented by the formula [X] wherein R⁵ is analkyl group can be obtained easily according to the usual method. Saidsalts may be the same as the salts mentioned as to the salts of thecompound represented by the formula [I]. The thus obtained compound ofthe formula [X] wherein R⁵ is an alkyl group and salts thereof can beisolated and purified in the well known manner. However, it is alsopossible to use them as the starting compound for the subsequentreaction without separating them.

(5) The compound represented by the formula [IVa] or its salt isobtained by reacting the compound represented by the formula [X] or itssalt with a halogenating agent in route 2. As the halogenating agent,there may be used halogens such as chlorine, bromine, iodine or thelike; sulfuryl halides such as sulfuryl chloride or the like; haloimidecompounds such as N-bromosudcinimide, N-chlorosuccinimide or the like;and halogen-pyridine complexes such as pyridinium hydrobromideperbromide or the like. The amount of the halogenating agent used inusually about 1 to several moles per mole of the compound represented bythe formula [X]or its salt. Said reaction is preferably conducted in thepresence of a Lewis acid such as aluminum chloride, boron trifluoride,titanium tetrachloride or the like. As the solvent, any solvent may beused as far as it does not adversely affect the reaction, and there maybe used, for example, tetrahydrofuran, dioxane, chloroform, methylenechloride, benzene or the like alone or in admixture of two or more. Thereaction may be conducted with cooling or at an elevated temperature fora period of 10 minutes to 24 hours.

(6) In the oximination reaction of route 4, a compound represented bythe formula [V] or its salt is reacted with a compound represented bythe formula [XIV] or its salt to obtain a compound of the formula [Ic]or its salt. The salt of the compound represented by the formula [XIV]includes the salts at basic group as mentioned hereinbefore. Thisreaction is usually carried out in a solvent such as water, an alcoholor the like or in other solvents which do not adversely affect thereaction or in a solvent mixture comprising them, and the reaction isusually carried out at 0° to 100° C., preferably 10° to 50° C. When asalt of the compound of the formula [XIV] is used in this reaction, thereaction is preferably carried out in the presence of a base includingan inorganic base such as an alkali metal hydroxide (for example, sodiumhydroxide, potassium hydroxide or the like), an alkaline earth metalhydroxide (for example, magnesium hydroxide, calcium hydroxide or thelike), an alkali metal carbonate (for example, sodium carbonate,potassium carbonate or the like), an alkaline earth metal carbonate (forexample, magnesium carbonate, calcium carbonate or the like), an alkalimetal hydrogen carbonate (for example, sodium hydrogen carbonate,potassium hydrogen carbonate or the like), an alkaline earth metalphosphate (for example, magnesium phosphate, calcium phosphate or thelike) and an alkali metal hydrogen phosphate (for example, disodiumhydrogen phosphate, dipotassium hydrogen phosphate or the like) and anorganic base such as an alkali metal acetate (for example, sodiumacetate, potassium acetate or the like), a trialkylamine (for example,trimethylamine, triethylamine or the like), picoline,N-methylpyrrolidine, N-methylmorpholine,1,5-diazabicyclo[4,3,0]-5-nonene, 1,4-diazabicyclo[2,2,2]octane,1,5-diazabicyclo[5,4,0]-7-undecene and the like.

(7) The ring closure reactions of routes 2 and 3 can also be carried outin substantially the same manner. Thus, a compound represented by theformula [IV] (including [IVa]) or its salt is reacted with athioformamide or thiourea represented by the formula [XI] to obtain acompound represented by the formula [Ia] or [Ib], respectively, or asalt thereof. This reaction is usually carried out in a solvent. As thesolvent, any solvent may be used so far as it does not retard thisreaction. Examples of the solvent usable are water, methanol, ethanol,acetone, tetrahydrofuran, dioxane, N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidone and the like, and they areused either alone or in admixture of two or more. Though the addition ofa de-acidifying agent is not particularly necessary, the addition ofde-acidifying agent sometimes smoothens the progress of reaction so faras it gives no change to the cephalosporin skeleton. As thede-acidifying agent used for this purpose, there are inorganic andorganic bases such as alkali metal hydroxides, alkali metal hydrogencarbonates, triethylamine, pyridine, N,N-dimethylaniline and the like.The reaction is usually carried out at 0° to 100° C., preferably 10° to50° C. Usually, 1 to several equivalents of a thioformamide or thiourearepresented by the formula [XI] is used per equivalent of the compoundof the formula [IV] (including [IVa]). The reaction time is generally1-48 hours, preferably 1-10 hours. Further, the compounds of theformulas [Ia] and [Ib] can also be converted to the correspondingdesired compounds by carrying out the protection of carboxyl group, itsremoval or salt formation according to a conventional method. Further,when groups R¹, R² and R⁴ have a group active to this reaction, they canbe protected with a conventional protecting group in any manner at thetime of reaction, and the protecting group can be removed by aconventional method after the reaction. The objective compounds of theformula [Ia] or [Ib] or their salts, thus obtained, can be isolated bythe usual method.

(8) In route 5, a compound represented by the formula [Ie] or its saltis prepared from a compound represented by the formula [Id] or its salt.For this purpose, a compound represented by the formula [Id] or its saltis dissolved or suspended in a solvent inert to the reaction, such astetrahydrofuran, dioxane, ethylene glycol diethyl ether, methylenechloride, chloroform, diemthylformamide, N,N-dimethylacetamide,acetonitrile, methanol, ethanol or a mixture thereof.

To the resulting solution or suspension is added a compound representedby the formula [XV] together with a lower alcohol. The resulting mixtureis subjected to reaction, and the reaction mixture is then reacted witha halogenating agent. In this reaction, a lower alcohol is used inexcess and the amount of the compound [XV] used is preferably 2 to 6equivalents per equivalent of the compound [Id] used. The term "inexcess" means an amount of more than 1 equivalent per equivalent of thecompound [Id]. All of the above reactions are carried out at -120° to-10° C., preferably -100° to -50° C. A reaction time of 5 to 30 minutesis sufficient and the reaction is terminated by acidifying the reactionsystem.

The halogenating agent used in this method is generally known to be asource for supplying a positive halogen atom such as Cl⁺, Br⁺ or I⁺.Examples of such halogenating agents include halogens such as chlorine,bromine and the like; N-haloimides such as N-chlorosuccinimide,N-bromosuccinimide and the like; N-haloamides such as N-chloroacetamide,N-bromoacetamide and the like; N-halosulfonamides such asN-chlorobenzenesulfonamide, N-chloro-p-toluenesulfonamide and the like;1-halobenzotriazoles; 1-halotriazines; organic hypohalogenites such a astert.-butyl hypochlorite, tert.-butyl hypoiodite and the like;halohydantoins such as N,N-dibromohydantoin, and the like. Of thesehalogenating agents, tert.-butyl hypochlorite is preferred. Thehalogenating agent is used in an amount sufficient for supplying apositive halogen in an amount equivalent to that of the compound [Id].

Suitable acids for the termination of reaction are those which, whenadded to a cold reaction mixture, will not cause solidification of thereaction mixture or freezing of the reaction mixture into a heavyviscous mixture. Examples of the suitable acids are 98% formic acid,glacial acetic acid, trichloroacetic acid and methanesulfonic acid.

After the termination of the reaction, the excess halogenating agent canbe removed by treating with a reducing agent such as trialkyl phosphite,sodium thiosulfate, or the like.

When B is a hydrogen atom in the compounds represented by the formulas[IVa], [VIII] and [X] in route 2, the compound represented by theformula [IV] in route 3 and the compound represented by the formula [V]in route 4 and their salts, it is also possible to convert B to a loweralkoxy group in the same manner as in the above-mentioned alkoxylatingreaction in route 5 and then to subject the product to the subsequentreaction.

From the reaction routes discussed in detail hereinbefore, it will beclear that there can easily be obtained the present compoundsrepresented by the formula [I] and salts thereof, the intermediateswhich are the compounds represented by the formulas [IIIb], [IV] and [V]and their salts, and other novel intermediates.

This invention will be explained below in more detail referring toReferential Examples, Examples and Preparation Examples, which are notby way of limitation and merely by way of illustration.

REFERENTIAL EXAMPLE 1

(1) In 15 ml of anhydrous acetonitrile was suspended 2.72 g of7-aminocephalosporanic acid (hereinafter, simply referred to as 7-ACA),and to the resulting suspension was added 5.68 g of borontrifluoridediethyl ether complex to form a solution, after which thesolution was subjected to reaction at room temperature for 5 hours.After completion of the reaction, the solvent was removed bydistillation under reduced pressure, and the residue obtained wasdissolved in 20 ml of aqueous acetone (containing 50% by volume ofwater) and the pH thereof was adjusted to 3.5 with 28% by weight aqueousammonia with ice-cooling. The deposited crystals were collected byfiltration, washed successively with 5 ml of aqueous acetone containing50% by volume of water and 5 ml of acetone, and then dried, to obtain2.14 g (yield 79%) of 7-amino-3-acetamidomethyl-Δ³ -cephem-4-carboxylicacid having a melting point of 155° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C)═0 1795, 1640, 1610, 1520.

NMR(CF₃ COOD) ppm value: 2.37 (3H, s, --CH₃), 3.82 (2H, s, C₂ -H), 4.60##STR37## 5.41 (2H, bs, C₆ -H, C₇ -H).

(2) In 30 ml of methanol was suspended 2.71 g of7-amino-3-acetamidomethyl-Δ³ -cephem-4-carboxylic acid obtained in above(1), to which suspension 1.90 g of p-toluenesulfonic acid monohydratewas added to form a solution. Then, 4 g of diphenyldiazomethane wasslowly added to the solution at room temperature and the resultingmixture was subjected to reaction at that temperature for 30 minutes.After completion of the reaction, the solvent was removed bydistillation under reduced pressure, and the residue thus obtained wasdissolved in a mixed solvent of 20 ml of water and ml of ethyl acetate,and the pH of the solution was adjusted to 7.0 with sodium hydrogencarbonate. The deposited crystals were collected by filtration,thoroughly washed with water and dried, to obtain 2.84 g (yield 65%) ofdiphenylmethyl 7-amino-3-acetamidomethyl-Δ³ -cephem-4-carboxylate havinga melting point of 190°-194° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C)═0 1758, 1720, 1647.

NMR(CDCl₃) ppm value: 1.87 (3H s, --CH₃), 3.59 (2H, s, C₂ -H), 3.65,4.27 ##STR38## 4.71 (1H, d, J=5 Hz, C₆ -H), 4.89 (1H, d, J=5 Hz, C₇ -H),6.12 (1H, bs, --NHCO--), 6.90 (1H, s, --COOH<), ##STR39##

REFERENTIAL EXAMPLE 2

Reaction and treatments were carried out in the same manner as inReferential Example 1-(1), except that trifluoroacetic acid was used asthe reaction solvent. Thus, the products shown in Table 4 were obtained.

                                      TABLE 4                                     __________________________________________________________________________     ##STR40##                                                                                       Product                                                                 Acid or             Melting                                                                             IR(KBr)                                             acid                point cm.sup.-1 :                            Starting compound                                                                          complex                                                                             R.sup.10      (°C.)                                                                        ν.sub.C═O                       __________________________________________________________________________    Butyronitrile                                                                              *BF.sub.3.Et.sub.2 O                                                                CH.sub.2 CH.sub.2 CH.sub.3                                                                  168-170                                                                             1795, 1635,                                                             (decomp.)                                                                           1610, 1520                             2-Methylbutyronitrile                                                                      "                                                                                    ##STR41##    170-172 (decomp.)                                                                   1795, 1635, 1620, 1530                 3-Ethoxypropionitrile                                                                      "     CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.3                                                        173-175                                                                             1800, 1640,                                                             (decomp.)                                                                           1610, 1530                             Acrylonitrile                                                                              "     CHCH.sub.2    165-167                                                                             1800, 1650,                                                             (decomp.)                                                                           1615, 1525                             Cyanoacetic acid                                                                           "     CH.sub.2 COOH 192-195                                                                             1755, 1675,                                                             (decomp.)                                                                           1620, 1580                             Benzyl cyanide                                                                             "                                                                                    ##STR42##    185-190 (decomp.)                                                                   1795, 1635, 1620, 1520                 Ethyl cyanoacetate                                                                         "     CH.sub.2 COOCH.sub.2 CH.sub.3                                                               185-190                                                                             1785, 1730,                                                             (decomp.)                                                                           1610, 1530                             Chloroacetonitrile                                                                         "     CH.sub.2 Cl   185-190                                                                             1790, 1650,                                                             (decomp.)                                                                           1610, 1520                             2-Cyanofuran "                                                                                    ##STR43##    200-204 (decomp.)                                                                   1780, 1630, 1590, 1510                 Benzonitrile "                                                                                    ##STR44##    212-214 (decomp.)                                                                   1793, 1630, 1610, 1520                 2-Cyanothiophene                                                                           "                                                                                    ##STR45##    189-190 (decomp.)                                                                   1795, 1620, 1530                       p-Tolunitrile                                                                              "                                                                                    ##STR46##    173-178 (decomp.)                                                                   1790, 1630, 1615, 1530                 p-Anisonitrile                                                                             "                                                                                    ##STR47##    188-193 (decomp.)                                                                   1790, 1620, 1595, 1530                 p-Hydroxybenzonitrile                                                                      "                                                                                    ##STR48##    182-184 (decomp.)                                                                   1795, 1625, 1600, 1530                 p-Cyanobenzoic acid                                                                        "                                                                                    ##STR49##    178-183 (decomp.)                                                                   1800, 1700, 1630, 1530                 2-Cyano-5-methylfuran                                                                      "                                                                                    ##STR50##    188-190 (decomp.)                                                                   1780, 1630, 1600, 1530                 2-Cyano-3- methylthiophene                                                                 "                                                                                    ##STR51##    175-178 (decomp.)                                                                   1790, 1630, 1610, 1530                 2-Methyl-4-cyano-5- phenyl-1,2,3-triazole                                                  "                                                                                    ##STR52##    193-195 (decomp.)                                                                   1790, 1660, 1610, 1530                 3-Cyanocoumarin                                                                            "                                                                                    ##STR53##    197-199 (decomp.)                                                                   1790, 1710, 1640, 1600, 1530           3-Cyano-4-methylcoumarin                                                                   "                                                                                    ##STR54##    210-212 (decomp.)                                                                   1790, 1710, 1640, 1600, 1530           **Acetonitrile                                                                             Conc. CH.sub.3      155   1795, 1640,                                         sulfuric            (decomp.)                                                                           1610, 1520                                          acid                                                             __________________________________________________________________________     Note:-                                                                        *BF.sub.3.Et.sub.2 O means boron trifluoridediethyl ether complex             (hereinafter the same applies).                                               **The reaction was carried out in acetonitrile.                          

REFERENTIAL EXAMPLE 3

Reaction and treatments were carried out in the same manner as inReferential Example 1-(2) to obtain the compounds shown in Table 5.

                  TABLE 5                                                         ______________________________________                                         ##STR55##                                                                     ##STR56##                                                                    Compound   Melting point                                                      R.sup.10   (°C.)                                                                             IR(KBr) cm.sup.-1 : ν.sub.C═O                    ______________________________________                                         ##STR57## 167-169 (decomp.)                                                                        1755, 1718, 1642                                         ##STR58## 192-195 (decomp.)                                                                        1755, 1720, 1625                                         ##STR59## 218-220 (decom.)                                                                         1755, 1720, 1638                                        ______________________________________                                    

EXAMPLE 1

(1) In 13 ml of sulfolane was suspended 2.72 g of 7-ACA, and 14.2 g ofboron trifluoride-diethyl ether complex and 1.0 g of5-methyl-1,2,3,4-tetrazole were added to the resulting suspension, afterwhich the resulting mixture was subjected to reaction at roomtemperature for 17 hours. After completion of the reaction, the reactionmixture was thrown into 15 ml of ice water. The pH of the mixture wasadjusted to 3.5 with 28% by weight aqueous ammonia with ice-cooling. Thedeposited crystals were collected by filtration, washed successivelywith 5 ml of water and 5 ml of acetone and then dried, to obtain 1.76 gof a mixture of 7-amino-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylic acid and7-amino-3-[1-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylic acid in the form of crystals.

(2) In 18 ml of methanol was suspended 1.76 g of the crystals obtainedin above (1), and 1.13 g of p-toluenesulfonic acid monohydrate was addedto the suspension to form a solution, after which 4.6 g ofdiphenyldiazomethane was slowly added thereto. The resulting mixture wassubjected to reaction at room temperature for 15 minutes. Aftercompletion of the reaction, the solcent was removed by distillationunder reduced pressure. The residue thus obtained was dissolved in amixed solvent of 30 ml of ethyl acetate and 30 ml of water, and the pHof the resulting solution was adjusted to 8 with sodium hydrogencarbonate. Then, the organic layer was separated and dried on anhydrousmagnesium sulfate, and the solvent was removed by distillation underreduced pressure. The residue thus obtained was purified by columnchromatography (Wako silica gel C-200; developing solvent, benzene:ethylacetate=4:1 by volume) to obtain 0.79 g of diphenylmethyl7-amino-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate having a melting point of 157°-160° C. (decomp.)and 0.14 g of diphenylmethyl7-amino-3-[1-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate having a melting point of 92° C. (decomp.)

Diphenylmethyl 7-amino-3-]2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate:

IR(KBr) cm⁻¹ : ν_(C)═O 1770, 1720.

NMR(CDCl₃) ppm value: 1.75 (2H, bs, --NH₂), 2.48 (3H, s, --CH₃), 3.20(2H, s, C₂ -H), 4.70 (1H, d, J=5 Hz, C₆ -H), 4.87 (1H, d, J=5 Hz, C₇-H), 5.30, 5.72 ##STR60## 6.92 (1H, s, --CH<), 7.30 ##STR61##

Diphenylmethyl 7-amino-3-[1-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate:

IR(KBr) cm⁻¹ : ν_(C)═O 1770, 1725.

NMR(CDCl₃) ppm value: 1.80 (2H, s, --NH₂), 2.15 (3H, s, --CH₃), 3.30(2H, s, C₂ -H), 4.70 (1H, d, J=5 Hz, C₆ -H), 4.85 (1H, d, J=5 Hz, C₇-H), 5.00, 5.38 ##STR62## 6.90 (1H, s, --CH<), 7.30 ##STR63##

(3) In a mixed solvent of 0.5 ml of anisole and 5 ml of trifluoroaceticacid was dissolved 0.462 g of diphenylmethyl7-amino-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate, and the resulting solution was subjected toreaction at room temperature for 1 hour. After completion of thereaction, the solvent was removed by distillation under reducedpressure, and 10 ml of water and 10 ml of ethyl acetate were added tothe residue obtained. The pH thereof was adjusted to 8 with 28% byweight aqueous ammonia with ice-cooling. Then, the aqueous layer wasseparated and the pH thereof was adjusted to 3.5 with 2N hydrochloricacid with ice-cooling. The deposited crystals were collected byfiltration, washed successively with 5 ml of water and 5 ml of acetone,and then dried, to obtain 0.26 g of7-amino-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylic acid having a melting point of 178° C. (decomp.)

IR(KBr) cm⁻¹ : ν_(C)═O 1790, 1610, 1530.

NMR(CF₃ COOD) ppm value: 2.70 (3H, s, --CH₃), 3.73 (2H, s, C₂ -H), 5.40(2H, s, C₆ -H, C₇ -H), 5.80, 6.12 ##STR64##

In the same manner as above, from 0.462 g of diphenylmethyl7-amino-3-[1-(5-methyl-1,2,3,4-tetrazoyl)methyl]-Δ³-cephem-4-carboxylate was obtained 0.25 g of7-amino-3-[1-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylic acid having a melting point of 195° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1795, 1615, 1530.

NMR(CF₃ COOD) ppm value: 2.95 (3H, s, --CH₃), 3.90 (2H, bs, C₂ -H), 5.45(2H, s, C₆ -H, C₇ -H), 5.57, 5.92 ##STR65##

EXAMPLE 2

In 19 ml of trifluoroacetic acid was dissolved 2.72 g of 7-ACA, and 7.1g of boron trifluoride-diethyl ether complex and 0.75 g of1,2,4-triazole are added to the resulting solutoin. The resultingmixture was subjected to reaction at rrom temperature for 7 hours. Aftercompletion of the reaction, the solvent was removed by distillationunder reduced pressure, and 15 ml of water was added to the resultingresidue, and the pH of the resulting mixture was adjusted to 3.5 with28% by weight aqueous ammonia with ice-cooling. The deposited crystalswere collected by filtration, washed successively with 5 ml of water and5 ml of acetone and then dried, to obtain 2.5 g of7-amino-3-[1-(1,2,4-triazolyl)methyl]-Δ³ -cephem-4-carboxylic acidhaving a melting point of 149° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1790, 1610, 1530.

NMR(CF₃ COOD) ppm value: 4.00 (2H, bs, C₂ -H), 5.47 ##STR66## 8.70##STR67## 9.80 ##STR68##

EXAMPLE 3

Using the following tetrazoles, reaction and treatments were carried outin the same manner as in Example 1-(1) or Example 2 to obtain theresults shown in Table 6. Subsequently, the products of Table 6 wereesterified and thereafter de-esterified in the same manner as in Example1-(2) and (3) to obtain the esters and carboxylic acids shown in Table7.

                                      TABLE 6                                     __________________________________________________________________________                                            Crude product                          ##STR69##           (g)Reaction conditionsBF.sub.3. Et.sub.2 O(ml)solvent                        eaction(°C.)temp.Reaction(hr)timeReaction                                                   ##STR70##                            __________________________________________________________________________    2.72 CH.sub.2 COOCH.sub.2 CH.sub.3                                                            1.72                                                                              7.1 CF.sub.3 COOH 19                                                                    Room temp.                                                                         7    0.8                                                                                 ##STR71##                       2.72                                                                                ##STR72## 1.6 7.1 CF.sub.3 COOH 19                                                                    Room temp.                                                                         7    0.85                                                                                ##STR73##                       2.72 H          0.77                                                                              7.1 Sulfolane 13                                                                        Room temp.                                                                         7    1.4*                                                                                ##STR74##                       2.72 Br         1.65                                                                              7.1 CF.sub.3 COOH 19                                                                    Room temp.                                                                         7    2.2*                                                                                ##STR75##                       2.72 SCH.sub.3  1.3 7.1 CF.sub.3 COOH 19                                                                    Room temp.                                                                         7    2.0*                                                                                ##STR76##                       2.72 NH.sub.2   0.94                                                                              7.1 CF.sub.3 COOH 19                                                                    Room temp.                                                                         7    1.3                                                                                 ##STR77##                       2.72 CH.sub.2 CH.sub.3                                                                        1.08                                                                              14.2                                                                              Sulfolane 13                                                                        50   7    1.36*                                                                               ##STR78##                       2.72 COOCH.sub.2 CH.sub.3                                                                     1.56                                                                              7.1 Sulfolane 13                                                                        50   7    2.86*                                                                               ##STR79##                       2.72 NHCOCH.sub.3                                                                             1.4 7.1 CF.sub.3 COOH 19                                                                    Room temp.                                                                         7    1.0                                                                                 ##STR80##                       __________________________________________________________________________     Note:                                                                         *These were obtained in the form of a mixture of 1substituted and             2substituted products. Such crude products were reacted and treated in th     same manner as in Example 1(2) to isolate the esters of the respective        1substituted and 2substituted products. The properties of these compounds     are shown in Table 7.                                                    

                                      TABLE 7                                     __________________________________________________________________________               ##STR81##                                                                                                ##STR82##                                         Melting                                                                             IR(KBr)              Melting                                                                             IR(KBr)                                      point cm.sup.-1 :                                                                        NMR(CDCl.sub.3) point cm.sup.-1 :                                                                        NMR(CF.sub.3 COOD)            R.sup.2   (°C.)                                                                        ν.sub.C═O                                                                   ppm value:      (°C.)                                                                        ν.sub.C═O                                                                   ppm value:                    __________________________________________________________________________     ##STR83##                                                                              107- 110 (decomp.)                                                                  1770, 1725                                                                          ##STR84##      177 (decomp.)                                                                       1795, 1735, 1610, 1535                                                              ##STR85##                                          ##STR86##                                                ##STR87##                                                                              73-75 (decomp.)                                                                     1770, 1725                                                                          ##STR88##      171 (decomp.)                                                                       1790, 1610, 1530                                                                    ##STR89##                     ##STR90##                                                                              79-83 (decomp.)                                                                     1770, 1720                                                                          ##STR91##      220 (decomp.)                                                                       1800, 1610, 1530                                                                    ##STR92##                                          ##STR93##                                                ##STR94##                                                                              75-78 (decomp.)                                                                     1770, 1720                                                                         1.87 (2H, s, NH.sub.2), 3.24 (2H, s, C.sub.2H), 4.68                          (1H, d, J=5Hz, C.sub.6H), 4.87 (1H, d, J=5Hz,                                 C.sub.7), 5.30, 5.77 (2H, ABq,                                                                165 (decomp.)                                                                       1790, 1610, 1530                                                                    ##STR95##                                          ##STR96##                                                ##STR97##                                                                              96-98 (decomp.)                                                                     1770, 1720                                                                         1.85 (2H, s, NH.sub.2), 3.20 (2H, s, C.sub.2H), 4.75                          (1H, d, J=5Hz, C.sub.6H), 4.88 (1H, d, J=5Hz,                                 C.sub.7), 5.03, 5.67 (2H, ABq,                                                                --    --   --                                                  ##STR98##                                                ##STR99##                                                                              64-68 (decomp.)                                                                     1770, 1720                                                                         1.95 (2H, bs, NH.sub.2), 2.58 (3H, s, SCH.sub.3),                             3.18 (2H, s, C.sub.2H), 4.60 (1H, d,                                          J=5Hz, C.sub.6H), 4.80 (1H, d, J=5Hz, C.sub.7H),                              5.25, 5.72 (2H, ABq,                                                                          195 (decomp.)                                                                       1790, 1610, 1530                                                                    ##STR100##                                         ##STR101##                                               ##STR102##                                                                             158-162 (decomp.)                                                                   1760, 1710                                                                         1.75 (2H, bs, NH.sub.2), 2.58 (3H, s, SCH.sub.3),                             3.10 (2H, s, C.sub.2H), 4.60 (1H, d,                                          J=5Hz, C.sub.6H), 4.80 (1H, d, J=5Hz, C.sub.7H),                              4.97, 5.47 (2H, ABq,                                                                          174 (decomp.)                                                                       1795, 1610, 1530                                                                    ##STR103##                                         ##STR104##                                               ##STR105##                                                                             115 (decomp.)                                                                       1770, 1720                                                                          ##STR106##     195 (decomp.)                                                                       1795, 1615, 1530                                                                    ##STR107##                                         ##STR108##                                               ##STR109##                                                                             142-143 (decomp.)                                                                   1775, 1725                                                                          ##STR110##     198-202 (decomp.)                                                                   1795, 1615, 1530                                                                    ##STR111##                                         ##STR112##                                               ##STR113##                                                                             82-83 (decomp.)                                                                     1770, 1720                                                                          ##STR114##     195-197 (decomp.)                                                                   1795, 1610, 1530                                                                    ##STR115##                                         ##STR116##                                               ##STR117##                                                                             165-167 (decomp.)                                                                   1775, 1735, 1710                                                                    ##STR118##     158 (decomp.)                                                                       1800, 1735, 1610, 1530                                                              ##STR119##                                         ##STR120##                                               ##STR121##                                                                             140-142 (decomp.)                                                                   1770, 1735, 1720                                                                    ##STR122##     142 (decomp.)                                                                       1800, 1740, 1610, 1530                                                              ##STR123##                                         ##STR124##                                               ##STR125##                                                                             106-108 (decomp.)                                                                   1770, 1720, 1700                                                                   1.95 (2H, bs, NH.sub.2), 2.20 (3H, s, COCH.sub.3),                            3.20 (2H, bs, C.sub.2H), 4.67 (1H, d, J=5Hz,                                  C.sub.6H), 4.82 (1H, d, J=5Hz, C.sub.7H), 5.32, 5.68                          (2H, ABq, J=16Hz,                                                                             179 (decomp.)                                                                       1790, 1690, 1610, 1530                                                              ##STR126##                                         ##STR127##                                               ##STR128##                                                                             147-150 (decomp.)                                                                   1770, 1720                                                                          ##STR129##     --    --   --                                                  ##STR130##                                              __________________________________________________________________________     Note:                                                                         *Solvent for measurement, d.sub.6 -DMSO                                  

EXAMPLE 4

Using the following triazoles, reaction and treatments were carried outin the same manner as in Example 1-(1) or Example 2 to obtain thecompounds shown in Table 8. The carboxylic acids were esterified in thesame manner as in Example 1-(2) to obtain the compounds shown in Table9. (2.72 g of 7-ACA was used as the starting material.)

                                      TABLE 8                                     __________________________________________________________________________     ##STR131##                                                                   Starting             Melting                                                                             IR(KBr)    * CF.sub.3 COOD                         triazole                                                                              Compound (g) point cm.sup.-1 :                                                                        NMR                ppm value                  (g)     R.sup.2      (°C.)                                                                        ν.sub.C═0                                                                         ** CF.sub.3 COOD + D.sub.2 O            __________________________________________________________________________    3-Methyl- 1,2,4- triazole 0.91                                                         ##STR132##  195 (decomp.)                                                                       1790, 1610, 1530                                                                    ##STR133##                                   3-Chloro- 1,2,4- triazole 1.14                                                         ##STR134##  191 (decomp.)                                                                       1790, 1610, 1530                                                                    ##STR135##                                   3-Acetamido- 1,2,4- traizole 2.52                                                      ##STR136##  150-155 (decomp.)                                                                   1795, 1680, 1610,  1540                                                             ##STR137##                                   3-Ethoxy- carbonyl- 1,2,4- triazole 1.55                                               ##STR138##  176 (decomp.)                                                                       1795, 1720, 1610, 1530                                                              ##STR139##                                   3-Methyl- thio-1,2,4- triazole 1.3                                                     ##STR140##  147 (decomp.)                                                                       1770, 1605, 1530                                                                    ##STR141##                                   4,5-Dimethoxy- carbonyl- 1,2,3- triazole 1.94                                          ##STR142##  161 (decomp.)                                                                       1795, 1725, 1610, 1530                                                              ##STR143##                                   4-Cyano-5- phenyl-1,2,3- triazole 1.9                                                  ##STR144##  204 (decomp.)                                                                       2220, (ν.sub.CN) 1790, 1610, 1530                                                ##STR145##                                   __________________________________________________________________________

                                      TABLE 9                                     __________________________________________________________________________     ##STR146##                                                                                  Melting                                                                             IR(KBr)                                                                 point cm.sup.-1 :                                              R.sup.2        (°C.)                                                                        ν.sub.C═O                                                                   NMR(CDCl.sub.3) ppm value:                          __________________________________________________________________________     ##STR147##    61-65 (decomp.)                                                                     1775, 1720                                                                          ##STR148##                                                                    ##STR149##                                                                    ##STR150##                                          ##STR151##    79-82 (decomp.)                                                                     1770, 1720                                                                         1.82 (2H, bs, NH.sub.2), 3.10 (2H, s,                                         C.sub.2H), 4.55 (1H, d, J=5Hz, C.sub.6H), 4.72                                (1H, d, J=5Hz, C.sub.7H), 4.70,                                                ##STR152##                                                                    ##STR153##                                                                    ##STR154##                                          ##STR155##    96-101 (decomp.)                                                                    1770, 1720                                                                         2.33 (2H, bs, NH.sub.2), 2.78, 3.21 (2H, ABq,                                 J=18Hz, C.sub.2H), 4.71 (1H, d, J=5Hz,                                        C.sub.6H), 4.90 (1H, d, J=5Hz, C.sub.7H), 5.32,                               5.92 (2H, ABq, J=16Hz,                                                         ##STR156##                                                                    ##STR157##                                          ##STR158##    90 (decomp.)                                                                        1770, 1720                                                                         2.32 (3H, s, CH.sub.3), 3.42 (2H, s, C.sub.2H),                               4.70 (1H, d, J=5Hz, C.sub.6H), 4.85 (1H, d,                                   J=5Hz, C.sub.7H),                                                              ##STR159##                                                                    ##STR160##                                          ##STR161##    167-168                                                                             1770, 1720                                                                          ##STR162##                                                                   d, J=5Hz, C.sub.6H), 4.80 (1H, d, J=5Hz,                                      C.sub.7),                                                                      ##STR163##                                                                    ##STR164##                                                                    ##STR165##                                          ##STR166##    80-84 (decomp.)                                                                     1770, 1720                                                                         1.90 (2H, bs, NH.sub.2), 2.50 (3H, s,                                         SCH.sub.3), 3.40 (2H, s, C.sub.2H), 4.65 (1H,                                 d, J=5Hz, C.sub.6H), 4.80 (1H, d, J=5Hz,                                      C.sub.7), 4.85 (2H, s,                                                         ##STR167##                                                                    ##STR168##                                         __________________________________________________________________________     Note:                                                                         *This compound was obtained by subjecting 4carboxy-1,2,3-triazole as the      starting compound to reaction and treatment in the same manner as in          Example 1(1) and (2).                                                    

EXAMPLE 5

The same reaction as in Example 1 was carried out under the conditionsshown in Table 10 to obtain the results shown in Table 10.

                                      TABLE 10                                    __________________________________________________________________________    Starting  Reaction conditions                                                 compound  Acid or       Reac-                                                                             Reac-                                                                             Crude                                                                             Esterification of                             5-Methyl-                                                                           acid   Reaction                                                                             tion                                                                              tion                                                                              pro-                                                                              crude product*.sup.5                      7-ACA                                                                             tetrazole                                                                           complex                                                                              solvent                                                                              temp.                                                                             time                                                                              duct                                                                              Ester of (a)*.sup.1 (g)                   (g) (g)   (g)    (ml)   (°C.)                                                                      (hr)                                                                              (g) Ester of (b)*.sup.2                       __________________________________________________________________________                                        (g)                                       2.72                                                                              1.0   BF.sub.3.Et.sub.2 O                                                                  Sulfolane                                                                            50   4  1.9*.sup.3                                                                        0.3/0.7                                             7.1    13                                                           "   "     BF.sub.3.Et.sub.2 O                                                                  Ethyl acetate                                                                        Room                                                                              20  2.1*.sup.3                                                                        0.95/0.15                                           14.2   27     temp.                                                 "   "     BF.sub.3.Et.sub.2 O                                                                  Nitromethane                                                                         Room                                                                              20  1.5*.sup.3                                                                        0.63/0.1                                            14.2   27     temp.                                                 "   0.92  BF.sub.3.Et.sub.2 O                                                                  Trifluoroace-                                                                        Room                                                                               7  1.5*.sup.3                                                                        0.71/0.05                                           7.1    tic acid                                                                             temp.                                                                  19                                                           "   1.0   Conc. H.sub.2 SO.sub.4                                                               Acetic acid                                                                          60   4  0.4*.sup.3                                                                         0.1/0.03                                           2.5    27                                                           "   1.26  BF.sub.3                                                                             Ethyl chloro-                                                                        Room                                                                              16  1.44*.sup. 4                                                                      --                                                  3.39   acetate                                                                              temp.                                                                  15                                                           "   2.52  BF.sub.3                                                                             Ethyl chloro-                                                                        Room                                                                              16  1.28*.sup.4                                                                       --                                                  6.78   acetate                                                                              temp.                                                                  30                                                           __________________________________________________________________________     Note:                                                                         *.sup.1 (a):                                                                  7Amino-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ.sup.3                -cephem-4-carboxylic acid                                                     *.sup.2 (b):                                                                  7Amino-3-[1-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ.sup.3                -cephem-4-carboxylic acid                                                     *.sup.3 The crude product was a mixture of (a) and (b).                       *.sup.4 The crude product was composed only of (a).                           *.sup.5 The crude product obtained by the reaction was subjected to           reaction and treatment in the same manner as in Example 1-(2) to obtain       the benzhydryl ester of each of (a) and (b).                             

EXAMPLE 6

The same reaction as in Example 2 was carried out under the conditionsshown in Table 11 to obtain the results shown in Table 11.

                                      TABLE 11                                    __________________________________________________________________________    Starting                                                                      compound                                                                             Reaction conditions                                                    1,2,4- Acid or       Reac-                                                                             Reac-                                                                             Product                                              Tria-                                                                            acid   Reaction                                                                             tion                                                                              tion               Melting                           7-ACA                                                                             zole                                                                             complex                                                                              solvent                                                                              temp.                                                                             time           Yield                                                                             point                             (g) (g)                                                                              (g)    (ml)   (°C.)                                                                      (hr)                                                                              Name of compound                                                                         (g) (°C.)                      __________________________________________________________________________    2.72                                                                              0.75                                                                             BF.sub.3.Et.sub.2 O                                                                  CH.sub.3 CN                                                                          Room                                                                              7   7-Amino-3-[1-(1,2,4-                                                                     2.02                                                                              149                                      7.1    20     temp.   triazolyl)methyl]-                                                                           (decomp.)                                                      Δ.sup.3 -cephem-4-carboxy-                                              lic acid                                         "   "  BF.sub.3.Et.sub.2 O                                                                  CHCl.sub.2 COOH                                                                      Room                                                                              "   7-Amino-3-[1-(1,2,4-                                                                     2.0 149                                      7.1    8      temp.   triazolyl)methyl]-                                                                           (decomp.)                                                      Δ.sup.3 -cephem-4-carboxy-                                              lic acid                                         "   "  Conc. H.sub.2 SO.sub.4                                                               CHCl.sub.2 COOH                                                                      Room                                                                              "   7-Amino-3-[1-(1,2,4-                                                                     0.34                                                                              149                                      5      8      temp.   triazolyl)methyl]-                                                                           (decomp.)                                                      Δ.sup.3 -cephem-4-carboxy-                                              lic acid                                         "   "  CH.sub.3 SO.sub.3 H                                                                  CF.sub.3 COOH                                                                        Room                                                                              "   7-Amino-3-[1-(1,2,4-                                                                     1.31                                                                              149                                      9.6    19     temp.   triazolyl)methyl]-                                                                           (decomp.)                                                      Δ.sup.3 -cephem-4-carboxy-                                              lic acid                                         "   "  FSO.sub.3 H                                                                          CH.sub.3 COOH                                                                        Room                                                                              24  7-Amino-3-[1-(1,2,4-                                                                     1.12                                                                              149                                      8      25     temp.   triazolyl)methyl]-                                                                           (decomp.)                                                      Δ.sup.3 -cephem-4-carboxy-                                              lic acid                                         "   "  CF.sub.3 SO.sub.3 H                                                                  CH.sub.3 COOH                                                                        Room                                                                              "   7-Amino-3-[1-(1,2,4-                                                                     1.05                                                                              149                                      12     25     temp.   triazolyl)methyl]-                                                                           (decomp.)                                                      Δ.sup.3 -cephem-4-carboxy-                                              lic acid                                         *2.88                                                                             0.76                                                                             BF.sub.3.Et.sub.2 O                                                                  CF.sub.3 COOH                                                                        Room                                                                              7   7-Amino-3-[1-(1,2,4-                                                                     1.77                                                                              149                                      7.1    23     temp.   triazolyl)methyl]-                                                                           (decomp.)                                                      Δ.sup.3 -cephem-4-carboxy-                                              lic acid                                         __________________________________________________________________________     Note:                                                                         *7-Amino-3-acetoxymethyl-Δ.sup.3 -cephem-4-carboxylic acid1-oxide       was used as the starting material.                                       

EXAMPLE 7

The same reaction and treatment as in Example 2 were repeated, exceptthat 7-ACA was replaced by the starting compounds shown in Table 12, toobtain the products shown in Table 12.

                  TABLE 12                                                        ______________________________________                                                                 Melting    IR (KBr)                                                           point      cm.sup.-1 :                               Starting compound                                                                         Product      (°C.)                                                                             ν.sub.C=0                              ______________________________________                                        p-Nitrobenzyl 7-                                                                          p-Nitrobenzyl 7-                                                                           114-116    1770,                                     amino-3-acetoxy-                                                                          amino-3-[1-  (decomp.)  1708                                      methyl-Δ.sup.3 -cephem-                                                             (1,2,4-triazo-                                                    4-carboxylate                                                                             lyl)methyl]-Δ.sup.3 -                                                   cephem-4-                                                                     carboxylate                                                       Ethyl 7-amino-3-                                                                          Ethyl 7-amino-3-                                                                           68-72      1770,                                     acetoxymethyl-Δ.sup.3 -                                                             [1-(1,2,4-tria-                                                                            (decomp.)  1720                                      cephem-4-carboxy-                                                                         zolyl)methyl]-                                                    late        Δ.sup.3 -cephem-4-                                                      carboxylate                                                       Diphenylmethyl 7-                                                                         7-Amino-3-[1-                                                                              149        1790,                                     amino-3-acetoxy-                                                                          (1,2,4-tria- (decomp.)  1610,                                     methyl-Δ.sup.3 -cephem-                                                             zolyl)methyl]-                                                                             (decomp.)  1530                                      4-carboxylate                                                                             Δ.sup.3 -dephem-4-                                                      carboxylic acid                                                   ______________________________________                                    

EXAMPLE 8

(1) In 40 ml of anhydrous methylene chloride was dissolved 2.72 g of2-(2-tert.-amyloxycarboxamidothiazol-4-yl)-acetic acid, and 1.06 g ofN-methylmorpholine was added to the solution, after which the reactionmixture was cooled to -35° C. Then, 1.12 g of ethyl chlorocarbonate wasadded thereto and reaction was effected at -35° C. to -25° C. for 1.5hours. To the reaction mixture was added 4.62 g of diphenylmethyl7-amino-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate, and the reaction was effected at -30° C. to -20°C. for 1 hour and then at -10° C. to +10° C. for 1 hour. Aftercompletion of the reaction, the solvent was removed by distillationunder reduced pressure. The residue thus obtained was dissolved in amixture of 40 ml of ethyl acetate and 30 ml of water. The organic layerwas separated, again mixed with 30 ml of water and adjusted to a pH of1.5 with 2N hydrochloric acid with ice-cooling. The organic layer wasseparated, mixed with 30 ml of water and adjusted to a pH of 7.0 withsodium hydrogen carbonate with ice-cooling. The organic layer wasseparated and dried on anhydrous magnesium sulfate, after which thesolvent was removed by distillation under reduced pressure. Diethylether was added to the residue, and the resulting crystals werecollected by filtration. They were thoroughly washed with diethyl etherand dried to obtain 6.52 g (yield 91.1%) of diphenylmethyl7-[2-(2-tert.-amyloxycarboxamidothiazol-4-yl)acetamido]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate having a melting point of 103°-105° C. (decomp.)

IR (KBr) cm⁻¹ : ν_(C)═O 1780, 1720, 1675. ##STR169##

In 30 ml of anhydrous benzene was suspended 2.72 g of2-(2-tert.-amyloxycarboxamidothiazol-4-yl)acetic acid, and 2.54 g ofoxazolyl chloride was added to the suspension with ice-cooling, afterwhich the resulting mixture was subjected to reaction at the sametemperature for one hour. After completion of the reaction, the solventwas removed by distillation under reduced pressure, and the resultingresidue was dissolved in 5 ml of anhydrous methylene chloride. Theresulting solution was dropped into a solution of 4.62 g ofdiphenylmethyl 7-amino-3-[2-(5-methyl- 1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate and 1.21 g of dimethylaniline in 40 ml ofanhydrous methylene chloride at -50° to -45° C. After completion of thedropping, the resulting mixture was subjected to reaction at -40° C. for30 minutes, at -20° C. to -10° C. for 30 minutes, and then at 0° C. for30 minutes. After completion of the reaction, the solvent was removed bydistillation under reduced pressure, and the resulting residue wasdissolved in 40 ml of ethyl acetate and 30 ml of water, after which theorganic layer was separated. To the organic layer was added again 30 mlof water, and the pH of the resulting mixture was adjusted to 1.5 with 2N hydrochloric acid with ice-cooling. The organic layer was subsequentlyseparated, and 30 ml of water was added thereto, after which the pH ofthe resulting mixture was adjusted to 7.0 with sodium hydrogen carbonatewith ice-cooling. The organic layer was separated, and dried onanhydrous magnesium sulfate, after which the solvent was removed bydistilllation under reduced pressure. Diethyl ether was added to theresulting residue, and the crystals precipitated were collected byfiltration, thoroughly washed with diethyl ether and then dried, toobtain 6.69 g (yield 93.5%) of diphenylmethyl 7-[2-(2-tert.-amyloxycarboxamidothiazol-4-yl)acetamido]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)mathyl]-Δ3-cephem-4-carboxylatehaving a melting point of 103°-105° C. (decomp.).

The physical properties (IR and NMR) of this compound were identicalwith those of the compound obtained above.

(2) In a mixed solvent of 32 ml of trifluoroacetic acid and 10 ml ofanisole was dissolved 6.52 g of diphenylmethyl7-[2-(2-tert.-amyloxycarboxamidothiazol-4-yl)acetamide]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate obtained in above (1). The solution was subjectedto reaction at room temperature for 2 hours. After completion of thereaction, the solvent was removed by distillation under reducedpressure. Diethyl ether was added to the residue, and the resultingcrystals were collected by filtration, washed thoroughly with diethylether and dried, to obtain 4.61 g (yield 92.1%) of trifluoroacetic acidsalt of7-[2-(2-aminothiazol-4-yl)acetamido]3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylic acid having a melting point of 184°-187° C.(decomp.).

IR(KBr) cm ^(-1:) ν_(C=0) 1765, 1655, 1630. NMR(d₆ -DMSO) ppm value:2.43 ##STR170## 3.45 (4H, bs, C₂ -H), ##STR171## 5.08 (1H, d, J=4 Hz, C₆-H), 5.50-590 ##STR172## 6.37 ##STR173## 8.96 (1H, d, J=8 Hz, --CONH--).

In the same manner as above, the following compound was obtained:

Trifluoroacetic acid salt of7[2-(2-aminothiazol-4-yl)acetamido]-3-acetamidomethyl-Δ³-cephem-4carboxylic acid

Melting point: 153°-154° C. (decomp.)

(3) In 50 ml of water was suspended 5.5 g of trifluoroacetic acid saltof7-[2-(2-aminothiazol-4yl)acetamido]-3-[2-(5-methyl-1,2,3-tetrazolyl)methyl]-Δ³-cephem-4-carboxylic acid, and 20 ml of 1 N aqueous solution of sodiumhydroxide was slowly added to the suspension with ice-cooling. Thereaction mixture was purified by a column chromatography with AmberliteXAD-2 (eluent: water) and the eluate was evaporated to dryness, toobtain 4.1 g (yield 88.4%) of sodium7-[2-2-aminothiazol-4-yl)acetamido]-3-[2-(5-methyl1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate having a melting point of 182°-187° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 0 1760, 1660, 1610.

NMR(d₆ -DMSO) ppm value: 2.41 (3H, s, --CH₃), 3.40 (2H, bs, C₂ -H), 3.62##STR174## 4 93 (1H, d, J=5 Hz, C₆ -H), 5.25-6.02 ##STR175## 6.09##STR176## 8.80 (1H, d, J=8 Hz, --CONH--).

In the same manner as above, the following compound was obtained:

Sodium 7-[2-(2-aminothiazol-4-yl)acetamido]-3-acetamidomethyl-Δ³-cephem-4-carboxylate

Melting point: 155°-158° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1755, 1680 - 1590.

NMR(D₂ O) ppm value: 1.98 (3H, s, --COCH₃), 3.16, 3.56 (2H, ABq, J=16Hz, C₂ -H), 3.52 ##STR177## 3.84, 4.15 ##STR178## 5.02 (1H, d, J=5 Hz,C₆ -H), 5.57 (1H, d, J=5 Hz, C₇ -H), 6.40 ##STR179##

EXAMPLE 9

(1) In 30 ml of anhydrous methylene chloride was dissolved 2.72 g of2-(2-tert.-amyloxycarboxamidothiazol-4-yl)-acetic acid, and 1.06 g ofN-methylmorpholine was added thereto, after which the reaction mixturewas cooled to -35° C. Then, 1.12 g of ethyl chlorocarbonate was addedand the reaction was effected at -35° C. to -25° C. for 1.5 hours, afterwhich the reaction mixture was cooled to -40° C. On the other hand, 2.96g of 7-amino-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]Δ³-cephem-4-carboxylic acid was suspended in 30 ml of anhydrous methylenechloride, and 6.1 g of N,O-bis(trimethylsilyl)acetamide was added to thesuspension with ice-cooling, after which the resulting mixture wassubjected to reaction at 5°-10° C. for 40 minutes until it became ahomogenerous solution. The solution was dropped into the reactionmixture prepared above while keeping the temperature at -40° C. to -30°C. After the dropping, the mixture was subjected to reaction at -30° C.to -20° C. for 1 hour and then at -10° C. to +10° C. for 1 hour. Aftercompletion of the reaction, the solvent was removed by distillationunder reduced pressure, 40 ml of ethyl acetate and 40 ml of water wereadded to the residue to dissolve the latter, and the pH thereof wasadjusted to 7.5 with sodium hydrogen carbonate with ice-cooling. Theaqueous layer was separated, mixed with 40 ml of ethyl acetate andadjusted to a pH of 2.0 with 2 N hydrochloric acid with ice-cooling.Then, the organic layer was separated, washed with 30 ml of water anddried on anhydrous magnesium sulfate, after which the solvent wasremoved by distillation under reduced pressure, to obtain 5.07 g (yield92.2%) of 7-[2-(2-tert.-amyloxycarboxamido-thiazol-4-yl)acetamido]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ.sup.3-cephem-4-carboxylic acid having a melting point of 138°-142° C.(decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1775, 1720, 1675. ##STR180##

(2) In a mixed solvent of 25 ml of trifluoroacetic acid and 8 ml ofanisole was dissolved 5.07 g of the7-[2-(2-tert.-amyloxycarboxamidothiazol-4-yl)acetamido]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]Δ³-cephem-4-carboxylic acid obtained in above (1). The resulting solutionwas subjected to reaction at room temperature for 30 minutes. Aftercompletion of the reaction, the solvent was removed by distillationunder reduced pressure, and diethyl ether was added to the residue,after which the resulting crystals were collected by filtration,thoroughly washed with diethyl ether and dried to obtain 4.72 g (yield93.1%) of trifluoroacetic acid salt of7-[2-(2-aminothiazol-4-yl)acetamido]-³-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ ³ -cephem-4-carboxylic acidhaving a melting point of 184°-187° C. (decomp.).

The physical properties (IR and NMR) of this compound were identicalwith those of the product obtained in Example 8-(2).

EXAMPLE 10

(1) A solution of 0.46 g of chlorine in 5 ml of anhydrous carbontetrachloride was dropped at -30° C. into a solution of 0.55 g ofdiketene in 10 ml of anhydrous methylene chloride, and the resultingmixture was subjected to reaction at -30° C. to -20° C. for 30 minutesto obtain a solution of acid chloride. On the other hand, 2.12 g ofN,O-bis(trimethylsilyl)acetamide was added to a suspension of 1.48 g of7-amino-3-[2-(5-methyl-1,2,3.4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylic acid in 20 ml of anhydrous methylene chloride withice-cooling, and the reaction was effected at room temperature for 1hour, after which the reaction mixture was cooled to -40° C. Then, theacid chloride solution prepared above was dropped thereinto at thattemperature. After completion of the dropping, the temperature wasslowly elevated and the reaction was effected at 0°-5° C. for 1 hour.After completion of the reaction, the solvent was removed bydistillation under reduced pressure, and the residue was dissolved in 30ml of ethyl acetate and 20 ml of water, after which the organic layerwas separated, washed successively with 20 ml of water and 20 ml ofsaturated aqueous solution of sodium chloride, and dried on anhydrousmagnesium sulfate. The solvent was removed by distillation under reducedpressure. Diethyl ether was added to the residue and the resultingcrystals were collected by filtration, thoroughly washed with diethylether and dried, to obtain 1.85 g (yield 89.4%) of7-(4-chloro-3-oxobutyramido)-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-.DELTA.³-cephem-4-carboxylic acid having a melting point of 98°-101° C.(decomp.).

IR(KBr) cm-¹ : ν_(C)═O 1778, 1725, 1668.

NMR(d₆ -DMSO) ppm value: 2.44 (3H, s, --CH₃), 3.42 (2H, bs, C₂ -H 3.56(2H, s, --COCH₂ CO--), 4.52 (2H, s, --ClCH₂ --), 5 08 (1H, d, J=5Hz, C₆-H), 5.31-5.89 ##STR181## 8.99 (1H, d, J=8 Hz, --CONH--).

(2) In 5 ml of dimethylformamide were dissolved 0.82 g of the7-(4-chloro-3-oxobutyramido)-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-.DELTA.³-cephem-4-carboxylic acid obtained in above (1) and 0.167 g of thiourea,and the solution was subjected to reaction at room temperature for 2hours. After completion of the reaction, the reaction mixture was throwninto 5 ml of water, and the pH was adjusted to 5.0 with sodium hydrogencarbonate with ice-cooling. The resulting precipitate was collected byfiltration, washed successively with water, acetone and diethyl etherand dried to obtain 0.77 g (yield 88.3%) of7-[2-(2-aminothiazol-4-yl)acetamido]-3-[2-(5-methyl1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylic acid having a melting point of 203°-208° C.(decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1760, 1650, 1625.

NMR(d₆ -DMSO) ppm value: 2.34 (3H, s, --CH₃), 3.40 (4H, bs, C₂ -H),##STR182## 4.92 (1H, d, J=5 Hz, C₆ -H), 5.18-5.80 ##STR183## 6.10 1H, s,##STR184## 8.68 (1H, d, J=8 Hz, --CONH--).

By reacting thioformamide in place of thiourea in the above procedure,the following compound was obtained:

7[2-(thiazol-4-yl)acetamido]-3 [2-(5-methyl1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylic acid

Melting point: 140°-142° C.(decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1775, 1720, 1660.

NMR(d₆ -DMSO) ppm value: 2.44 (3H, s, --CH₃), 3.44 (2H, bs, C₂ -H), 3 79##STR185## 5.06 (1H, d, J=5 Hz, C₆ -H), 5.60 ##STR186## 5.6-5.8 (1H, m,C₇ -H), 7.45 ##STR187## 9.08 9.00-9.25 (1H, m, --CONH--).

1 EXAMPLE11

By subjecting the starting compounds shown in Table 13 to the samereaction as in Example 8, 9 or 10, the corresponding compounds shown inTable 13 were obtained.

                                      TABLE 13                                    __________________________________________________________________________     ##STR188##                                                                    R.sup.2Compound                                                                               point (°C.)Melting                                                           cm.sup.-1 :ν.sub.C═OIR(KBr)                                                  ##STR189##                                       __________________________________________________________________________     ##STR190##     115 (decomp.)                                                                       1780, 1670, 1630                                                                     ##STR191##                                        ##STR192##     152 (decomp.)                                                                       1775, 1670, 1630                                                                     ##STR193##                                        ##STR194##     137-140 (decomp.)                                                                   1770, 1740, 1670, 1630                                                               ##STR195##                                        ##STR196##     149-154 (decomp.)                                                                   1775, 1740, 1670, 1630                                                               ##STR197##                                        ##STR198##     133 (decomp.)                                                                       1770, 1670, 1630                                                                     ##STR199##                                        ##STR200##     148 (decomp.)                                                                       1778, 1710, 1668                                                                     ##STR201##                                        ##STR202##     100-102 (decomp.)                                                                   1780, 1710, 1670                                                                     ##STR203##                                        ##STR204##     143 (decomp.)                                                                       1770, 1690, 1665, 1630                                                               ##STR205##                                        ##STR206##     185 (decomp.)                                                                       1770, 1665, 1630                                                                     ##STR207##                                        ##STR208##     107 (decomp.)                                                                       1765, 1665, 1630                                                                     ##STR209##                                        ##STR210##     107 (decomp.)                                                                       1776, 1665,  1630                                                                    ##STR211##                                        ##STR212##     150-153 (decomp.)                                                                   1770, 1665, 1630                                                                     ##STR213##                                        ##STR214##     120-123 (decomp.)                                                                   1765, 1730, 1665, 1630                                                               ##STR215##                                        ##STR216##     119 (decomp.)                                                                       1770, 1660, 1630                                                                     ##STR217##                                        ##STR218##     1144-146 (decomp.)                                                                  1765, 1665, 1630                                                                     ##STR219##                                        ##STR220##     133 (decomp.)                                                                       1765, 1665, 1630                                                                     ##STR221##                                        ##STR222##     155-158 (decomp.)                                                                   1765, 1725, 1660, 1630                                                               ##STR223##                                        ##STR224##     140 (decomp.)                                                                       1765, 1665, 1630                                                                     ##STR225##                                        ##STR226##     137-140 (decomp.)                                                                   1775, 1730, 1640                                                                     ##STR227##                                        ##STR228##     153 (decomp.)                                                                       1770, 1670, 1630                                                                     ##STR229##                                        ##STR230##     180 (decomp.)                                                                       1770, 1690, 1670, 1630                                                              --                                                 ##STR231##     124-125 (decomp.)                                                                   1770, 1660, 1630                                                                     ##STR232##                                        ##STR233##     137-141 (decomp.)                                                                   1760, 1660, 1640                                                                     ##STR234##                                                                    ##STR235##                                        ##STR236##     105-108 (decomp.)                                                                   1765, 1660, 1640                                                                     ##STR237##                                        ##STR238##     114-116 (decomp.)                                                                   1765, 1660, 1640                                                                     ##STR239##                                        ##STR240##     175-176 (decomp.)                                                                   1780, 1710, 1665, 1660                                                               ##STR241##                                        ##STR242##     161-163 (decomp.)                                                                   1760, 1710˜1620                                                                ##STR243##                                        ##STR244##     155 (decomp.)                                                                       1760, 1660, 1630                                                                     ##STR245##                                        ##STR246##     184 (decomp.)                                                                       1765, 1710,˜1620                                                               ##STR247##                                        ##STR248##     151-153 (decomp.)                                                                   1768, 1705˜1620                                                                ##STR249##                                        ##STR250##     183-187 (decomp.)                                                                   1765, 1710˜1610                                                                ##STR251##                                       __________________________________________________________________________

1. EXAMPLE12

(1) A solution of 1.92 g of bromine in 12 ml of anhydrous methylenechloride was dropped at -30° C. into a solution of 1.26 g of diketene in20 ml of anhydrous methylene chloride, and the reaction was effected at-30° C. to -20° C. for 30 minutes. Then, the reaction mixture wasdropped into a solution of 4.62 g of diphenylmethyl7-amino-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate and 4 g of N,O-bis(trimethylsilyl)acetamide in 50ml of anhydrous chloroform at a temperature of -30° C. or below. Afterthe dropping, the mixture was subjected to reaction at -30° C. to -20°C. for 30 minutes and then at -10° C. to 0° C. for 1 hour. Aftercompletion of the reaction, the solvent was removed by distillationunder reduced pressure, the residue obtained was dissolved in 60 ml ofethyl acetate and 60 ml of water, and the organic layer was separated,washed successively with 30 ml of water and 30 ml of saturated aqueoussolution of sodium chloride, and dried on anhydrous magnesium sulfate,after which the solvent was removed by distillation under reducedpressure. Diethyl ether was added to the residue and the resultingcrystals were collected by filtration to obtain 5.92 g (yield 94.7%) ofdiphenylmethyl7-(4-bromo-3-oxobutyramido)3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-.DELTA.³-cephem-4-carboxylate having a melting point of 82°-85° C. (decomp.).

IR(KBr) cm⁻¹ 84 C═O 1780, 1722, 1690-1650.

NMR(CDCl₃) ppm value: 2.42 ##STR252## 3.19 (2H, bs, C₂ -H), 3.62 (2H, s,--COCH₂ CO--), 3.97 (2H, s, BrCH₂ -), 4.86 (1H, d, J=5Hz, C₆ -H),5.20-6.0 ##STR253## 6.89 (1H, s, >CH--), 7.25 ##STR254## 7.91 (1H, d,J=8 Hz, --CONH--).

(3) In 30 ml of N,N-dimethylformam:ide were dissolved 6.52 g ofdiphenylmethyl7-(4-bromo-3-oxobutyramido)-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-.DELTA.³-cephem-4-carboxylate and 1.67 g of N-phenylthiourea, and the solutionwas subjected to reaction at room temperature for 2 hours. Aftercompletion of the reaction, the solvent was removed by distillationunder reduced pressure, and the residue was washed with diethyl etherand then mixed with 100 ml of ethyl acetate and 50 ml of water. The pHof the mixture was adjusted to 7.5 with saturated aqueous solution ofsodium hydrogen carbonate with ice-cooling, after which the organiclayer was separated and dried on anhydrous magnesium sulfate. Thesolvent was removed by distillation under reduced pressure, to obtain5.9 g of diphenylmethyl7-[2-(2-phenylaminothiazol-4-yl)acetamido]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate as a crude solid product. Without purification, itwas dissolved in 59 ml of anisole, and then 59 ml of trifluoroaceticacid was dropped thereinto, after which the mixture was subjected toreaction at room temperature for 30 minutes. After completion of thereaction, the solvent was removed by distillation under reducedpressure, and diethyl ether was added to the residue, after which theresulting crystals were collected by filtration, thoroughly washed withdiethyl ether and dried to obtain trifluoroacetic acid salt of7-[2-(2-phenylaminothiazol-4-yl)acetamido]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methy.1]-Δ³ -cephem-4-carboxylic acidhaving a melting point of 165°-169° C. (decomp.)

IR(KBr) cm⁻¹ : ν_(C)═O 1775 1660, 1625. ##STR255##

EXAMPLE 13

In 27 ml of N,N-dimethylformamide was dissolved 5.5 g of the7-[2-(2-tert.-amyloxycarboxamidothiazol-4-yl)acetamido]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylic acid obtained in Example 9-(1). Then, 1 g oftriethylamine and 2.9 g of pivaloyloxymethyl iodide were added to thesolution with ice-cooling, and the resulting mixture was subjected toreaction for 30 minutes. After completion of the reaction, the reactionmixture was introduced into a mixed solvent of 250 ml of water and 250ml of ethyl acetate, and the pH thereof was adjusted to 7.0 with sodiumhydrogen carbonate. The organic layer was separated, washed with waterand dried on anhydrous magnesium sulfate. The solvent was removed bydistillation under reduced pressure, to obtain 6.02 g ofpivaloyloxymethyl7-[2-(2-tert.-amyloxycarboxamidothiazol-4-yl)acetamido]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate as a crude solid product. Without purification, itwas dissolved in 30 ml of trifluoroacetic acid and the solution wassubjected to reaction at room temperature for 30 minutes. Aftercompletion of the reaction, the solvent was removed by distillationunder reduced pressure, 80 ml of water and 80 ml of ethyl acetate wereadded to the residue obtained, and the pH thereof was adjusted to 7.0with sodium hydrogen carbonate with ice-cooling. The organic layer wasseparated and dried on anhydrous magnesium sulfate, and a solution of0.8 g of dry hydrogen chloride in 20 ml of diethyl ether was addedthereto with stirring while cooling the mixture with ice, upon whichwhite colored powder precipitated. It was collected by filtration,thoroughly washed with diethyl ether and recrystallized from ethylacetate to obtain 3.82 g of hydrochloride of pivaloyoxymethyl7-[2-(2-aminothiazol-4-yl)acetamido]-3-[2-(5-methyl1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate having a melting point of 146°-148° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1782, 1750, 1670.

NMR(d₆ -DMSO) ppm value: 1.15 (9H, s, --C(CH₃)₃), 2.46 ##STR256## 3.51(2H, s, C₂ -H), 3.62 ##STR257## 5.15 (1H, d, J-5 Hz, C₆ -H), 5.26-5.79##STR258## 5 87 (2H, s, --OCH₂ --), 6.62 ##STR259## 9.23 (1H, d, J=8 Hz,--CONH--).

EXAMPLE 14

By subjecting the starting compounds shown in Tables 14 and 15 to thesame reaction as in Example 13, the corresponding compounds shown inTables 14 and 15 were obtained.

                                      TABLE 14                                    __________________________________________________________________________     ##STR260##                                                                                Melting                                                                             IR(KBr)                                                    Compound     point cm.sup.-1 :                                                R.sup.2      (°C.)                                                                        ν.sub.C═O                                                                   NMR(*.sup.1 d.sub.6 -DMSO, *.sup.2 CDCl.sub.3,                                *.sup.3 D.sub.2 O) ppm value:                         __________________________________________________________________________     ##STR261##   124-127 (decomp.)                                                                  1780, 1750, 1670                                                                    ##STR262##                                            ##STR263##   112-115 (decomp.)                                                                  1780, 1750, 1670                                                                    ##STR264##                                                                    ##STR265##                                                                   9.19 (1H, d, J=8Hz, CONH)                              ##STR266##    165 (decomp.)                                                                     1780, 1750, 1680                                                                    ##STR267##                                                                    ##STR268##                                            ##STR269##   137-139 (decomp.)                                                                  1770, 1740, 1660                                                                    ##STR270##                                                                    ##STR271##                                                                    ##STR272##                                                                    ##STR273##                                            ##STR274##   120-132 (decomp.)                                                                  1770, 1745, 1660                                                                    ##STR275##                                                                    ##STR276##                                                                    ##STR277##                                            ##STR278##   135-138 (decomp.)                                                                   ##STR279##                                                                         ##STR280##                                           __________________________________________________________________________     Note:                                                                         *.sup.1, *.sup.2 and *.sup.3 mean that the respective solvents indicated      in the heading were used for measurement of NMR.                              *.sup.4 means that the NMR data are concerned with a compound to which HC     is not added.                                                            

                                      TABLE 15                                    __________________________________________________________________________     ##STR281##                                                                            Melting                                                                             IR(KBr)                                                                 point cm.sup.-1                                                      R.sup.1  (°C.)                                                                        ν.sub.C═O                                                                   NMR(d.sub.6 -DMSO) ppm value:                             __________________________________________________________________________    CH.sub.3 131-133 (decomp.)                                                                   1780, 1725, 1665                                                                    ##STR282##                                                                    ##STR283##                                                                    ##STR284##                                                                    ##STR285##                                                                   CONH)                                                      ##STR286##                                                                            152-153 (decomp.)                                                                   1780, 1750, 1680                                                                    ##STR287##                                                                    ##STR288##                                                                    ##STR289##                                                                    ##STR290##                                                                   CONH)                                                     __________________________________________________________________________     Note:-                                                                        *Hydrochloride-                                                          

EXAMPLE 15

(1) To a suspension of 2.96 g of7-amino-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylic acid in 15 ml of N,N-dimethylformamide was added1.34 g of salicylaldehyde, and the mixture was subjected to reaction atroom temperature for 1 hour. The reaction mixture was cooled with ice,and 0.96 g of triethylamine and 2.42 g of pivaloyloxymethyl iodide wereadded thereto, after which the resulting mixture was subjected toreaction for 20 minutes. After completion of the reaction, the reactionmixture was introduced into a mixed solvent of 150 ml of water and 150ml of ethyl acetate. After adjusting the pH to 7.3 with sodium hydrogencarbonate, the organic layer was separated, washed with two portions of100 ml of water, and dried on anhydrous magnesium sulfate. Then, thesolvent was removed by distillation under reduced pressure. Isopropylalcohol was added to the residue, and the resulting crystals werecollected by filtration, and then recrystallized from isopropyl alcohol,to obtain 2.73 g (yield 53.1%) of pivaloyloxymethyl7-(2-hydroxybenzylideneamino)-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-.DELTA.³-cephem-4-carboxylate having a melting point of 136°-137° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C=O) 1770, 1765-1750.

NMR(CDCl₃) ppm value: 1.23 (9H, s, --C(CH₃)₃), 2.51 ##STR291## 3.30 (2H,s, C₂ -H), 5.08 (1H, d, J=5 Hz, C₆ -H), 5.32 (1H, d, J=5 Hz, C₇ -H),5.38, 5.82 ##STR292## 5.91 (2H, bs, --OCH₂ O--), 6.70-7.50 ##STR293##8.49 (1H, s, --CH=N--).

(2) In a mixed solvent of 50 ml of 4 N hydrochloric acid and 25 ml ofdiethyl ether, 5.14 g of the pivaloyoxymethyl7-(2-hydroxy-benzylideneamino)-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-.DELTA.³-cephem-4-carboxylate obtained in above (1) was stirred for 1 hour at10°-15° C. Then, the aqueous layer was separated, and washed with twoportions of 30 ml of diethyl ether, after which 100 ml of diethyl etherwas added to the aqueous layer and the pH thereof was adjusted to 7.0with 28% by weight aqueous ammonia with ice-cooling. The organic layerwas separated and dried on anhydrous magnesium sulfate. Then, a solutionof 1 g of dry hydrogen chloride in 20 ml of diethyl ether was addedthereto with stirring with ice-cooling, upon which a white coloredpowder deposited. This was collected by filtration, thoroughly washedwith diethyl ether and recrystallized from chloroform, to obtain 3.67 g(yield 82.2%) of hydrochloride of pivaloyloxymethyl7-amino-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate having a melting point of 149°-151° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C=O) 1773, 1741, 1730.

NMR(d₆ -DMSO) ppm value: 1.18 (9H, s, --C(CH₃)₃), 2 44 ##STR294## 3.60(2H, s, C₂ -H), 5.23 (2H, s, C₆ -H, C₇ -H), 5.62 ##STR295## 5.78-5.92(2H, m, --COOCH₂ O--).

(3) In 20 ml of anhydrous methylene chloride was dissolved 1 g ofdiketene, and a solution of 0.85 g of chlorine in 9 ml of anhydrouscarbon tetrachloride was dropped thereinto at -30° C., after which themixture was subjected to reaction at -30° C. to -20° C. for 30 minutes.Then, the reaction mixture was dropped at -40° C. into a solution of4.47 g of the hydrochloride of pivaloyoxymethyl7-amino-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate obtained in above (2) and 2.43 g ofN,N-dimethylaniline in 50 ml of anhydrous methylene chloride. After thedropping, the temperature was slowly elevated and the mixture wassubjected to reaction at 0°-5° C. for 1 hour. After completion of thereaction, the solvent was removed by distillation under reducedpressure, and the residue was dissolved in 50 ml of ethyl acetate and 30ml of water. The organic layer was separated, washed successively withwater and saturated aqueous solution of sodium chloride, and dried onanhydrous magnesium sulfate, after which the solvent was removed bydistillation under reduced pressure to obtain an oily product. Then, 15ml of N,N-dimethylformamide was added to dissolve the oily product. Tothe solution was added 0.76 g of thiourea and the mixture was subjectedto reaction at room temperature for 2 hours. After completion of thereaction, the reaction mixture was introduced into a mixed solvent of150 ml of water and 150 ml of ethyl acetate, and the pH was adjusted to7.0 with sodium hydrogen carbonate, after which the organic layer wasseparated, dried on anhydrous magnesium sulfate and then concentratedunder reduced pressure until the volume of the organic layer reached 50ml. Then, a solution of dry hydrogen chloride in diethyl ether was addedthereto with stirring with ice-cooling, upon which a white coloredpowder deposited. This was collected by filtration, thoroughly washedwith diethyl ether and recrystallized from ethyl acetate, to obtain 4.4g (yield 75.0%) of hydrochloride of pivaloyloxymethyl7-[2-(2-aminothiazol-4-yl)acetamido]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³ -cephem-4-carboxylate having a melting point of 146°-148° C.(decomp.).

The physical properties (IR and NMR) of this compound were identicalwith those of the product of Example 13.

EXAMPLE 16

(1) By carrying out an acylating reaction in the same manner as inExample 9-(1), the following corresponding compound was obtained:

7-[2-(2-chloroacetamidothiazol-4-yl)acetamido]-3-[(3-chloro-1,2,4-triazolyl)methyl]-Δ³-cephem-4-carboxylic acid

Melting point: 120°-122° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C=O) 1775, 1710, 1680, 1650. NMR(d₆ -DMSO) ppm value:3.43 (2H, s, C₂ -H), 3.60 ##STR296## 4.32 (2H, s, ClCH₂ --), 5.09 (1H,d, J=5 Hz, C₆ -H), 5.05, 5.39 ##STR297## 5.68 (1H, dd, J=5 Hz, J=8 Hz,C₇ -H), 6.97 ##STR298## 8.03 ##STR299## 8.95 (1H, d, J=8 Hz, --CONH--).

(2) In 40 ml of dry methylene chloride was suspended 2.13 g of the7-[2-(2-chloroacetamidothiazol-4-yl)acetamido]-3-[(3-chloro-1,2,4-triazolyl)methyl]-Δ³ -cephem-4-carboxylic acidobtained in above (1), and 0.01 g of pyridinium p-toluenesulfonate and2.88 g of ethyl vinyl ether were added to the suspension, after whichthe resulting mixture was subjected to reflux to form a solution. Then,the solution was cooled to -75° C., to which 4.48 ml (2.675millimoles/ml) of a methanolic solution of lithium methoxide was added.After stirring for 5 minutes, 0.52 g of tert.-butyl hypochlorite wasadded and stirred at that temperature for 15 minutes. Then, 0.48 g ofacetic acid was added, and the temperature was elevated to -30° C.

After completion of the reaction, the solvent was removed bydistillation under reduced pressure, and 50 ml of ethyl acetate and 40ml of water were added to the residue thus obtained, after which the pHwas adjusted to 0.5 with 2 N hydrochloric acid with ice-cooling. Theorganic layer was separated and dried on anhydrous magnesium sulfate,and the sblvent was removed by distillation under reduced pressure.Diethyl ether was added to the residue thus obtained and the resultingcrystals were collected by filtration, to obtain 1.53 g (yield 68%) of7β-[2-(2-chloroactamidothiazol-4-yl)acetamido]-7α-methoxy-3-[(3-chloro-1,2,4-triazolyl)methyl]-Δ³-cephem-4-carboxylic acid having a melting point of 145°-150° C.(decomp.).

IR(KBr) cm⁻¹ : ν_(C=O) 1775, 1720, 1685, 1635.

NMR(d₆ -DMSO) ppm value: 3.34 (2H, s, C₂ -H), 3.38 (3H, s, --OCH₃), 3.64##STR300## 4.31 (2H, s, ClCH₂ --), 5.10-5.30 ##STR301## 6.91 ##STR302##7.96 ##STR303## 9.25 (1H, s, --CONH--).

(3)In 7 ml of N,N-dimethylacetamide was dissolved 1.40 g of7β-[2-(2-chloroacetamidothiazol-4-yl)acetamido]-7α-methoxy-3-[(3-chloro-1,2,4-triazolyl)methyl]-Δ³-cephem-4-carboxylic acid, and 0.3 g of thiourea was added to thesolution and reaction was effected at room temperature for 10 hours.After completion of the reaction, 50 ml of diethyl ether was added tothe reaction mixture and the supernatant was removed by decantation.Again, 50 ml of diethyl ether was added to the residue and the sameprocedure as above was repeated. Then, water was added to the residue,and the latter was disintegrated, after which the crystals werecollected by filtration and dried, to obtain 0.65 g (yield 50%) ofhydrochloride of7β-[2-(2-aminothiazol-4-yl)acetamino]-7α-methoxy-3-[(3-chloro-1,2,4-triazolyl)methyl]-Δ³-cephem-4-carboxylic acid having a melting point of 151°-156° C.(decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1765, 1660, 1610.

NMR(d₆ -DMSO) ppm value: 3.28 (2H, s, C₂ -H), 3.35 (3H, s, --OCH₃), 3.60##STR304## 5.05-5.30 ##STR305## 6.82 ##STR306## 7.95 ##STR307##

EXAMPLE 17

(1) In 16 ml of N,N-dimethylacetamide was dissolved 3.15 g of2-(2-tert.-amyloxycarboxamidothiazol-4-yl)-2-(syn)-methoxyiminoaceticacid, into which 1.69 g of phosphorus oxychloride was dropped at -20° C.The resulting mixture was stirred at that temperature for 1.5 hours, andthen dropped at -30° C. to -20° C. into a solution of 3.16 g of7-amino-3-[(3-chloro-1,2,4-triazolyl)methyl]-Δ³ -cephem-4-carboxylicacid and 6.1 g of N,O-bis(trimethylsilyl)acetamide in 32 ml of anhydrousmethylene chloride. After the dropping, the mixture was subjected toreaction at that temperature for 1 hour, then at 0°-10° C. for 30minutes, and then at room temperature for 30 minutes. After completionof the reaction, the methylene chloride was removed by distillationunder reduced pressure, and the residue thus obtained was introducedinto a mixed solvent of 80 ml of water and 100 ml of ethyl acetate. Theorganic layer was thereafter separated, and 80 ml of water was addedthereto, after which the pH thereof was adjusted to 7.0 with sodiumhydrogen carbonate. The aqueous layer was separated, and 80 ml of ethylacetate was added thereto, after which the pH was adjusted to 1.5 with2N hydrochloric acid with ice-cooling. The organic layer was separated,washed successively with 50 ml of water and 50 ml of saturated aqueoussolution of sodium chloride and dried on anhydrous magnesium sulfate,after which the solvent was removed by distillation under reducedpressure. Diethyl ether was added to the residue and the resultingcrystals were collected by filtration, to obtain 5.62 g (yield 91.8%) of7-[2-(2-tert.-amyloxycarboxamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[(3-chloro-1,2,4-triazolyl)methyl]-Δ³-cephem-4-carboxylic acid having a melting point of 198°-200° C.(decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1780, 1720, 1670

NMR(d₆ -DMSO) ppm value: 0.89 (3H, t, J=7 Hz, --CH₂ CH₃), 1.44##STR308## 1.78 (2H, q, J=7 Hz, --CH₂ CH₃), 3.45 (2H, bs, C₂ -H), 3.87(3H, s, --OCH₃), 4.96-5.40 ##STR309## 5.82 (1H, dd, J=5 Hz,.J=8 Hz, C₇-H), 7.24 ##STR310## 8.02 ##STR311## 9.61 (1H, d, J=8 Hz, --CONH--),11.79 (1H, bs, --CONH--).

(2) In 30 ml of trifluoroacetic acid was dissolved 5.62 g of the7-[2-(2-tert.-amyloxycarboxamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[(3-chloro-1,2,4-triazolyl)methyl]-Δ³-cephem-4-carboxylic acid obtained in above (1), and reaction waseffected at room temperature for 30 minutes. After completion of thereaction, the solvent was removed by distillation under reducedpressure. Diethyl ether was added to the residue, and the resultingcrystals were collected by filtration, thoroughly washed with diethylether and dried, to obtain 5.23 g (yield 93.1%) of trifluoroacetic acidsalt of7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[(3-chloro1,2,4-triazolyl)methyl]-Δ³-cephem-4-carboxylic acid having a melting point of 162° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1778, 1715, 1670, 1630.

NMR(d₆ -DMSO) ppm value: 3.48 (2H, bs, C₂ -H), 3.93 (3H, s, --OCH ),4.98-5.42 ##STR312## 5078 (1H, dd, J=5 Hz, J=8 Hz, C₇ -H, ##STR313##8.02 ##STR314## 9.74 (1H, d, J=8 Hz, --CONH--).

EXAMPLE 18

(1) In 40 ml of anhydrous methylene chloride was dissolved 3.15 g of2-(2-tert.-amyloxycarboxamidothiazol-4-yl)-2-(syn)-methoxyiminoaceticacid, and 1.06 g of N-methylmorpholine was added thereto, after whichthe reaction mixture was cooled to -35° C. Then, 1.12 g of ethylchlorocarbonate was added thereto and the resulting mixture wassubjected to reaction at -35° C. to -25° C. for 1.5 hours, after which4.62 g of diphenylmethyl7-amino-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate was added to the reaction mixture and theresulting mixture was subjected to reaction at -30° C. to -20° C. for 1hour. Then, the temperature was slowly elevated, and the reaction wasadditionally carried out at room temperature for 3 hours. Aftercompletion of the reaction, the solvent was removed by distillationunder reduced pressure. To the residue were added 50 ml of ethyl acetateand 40 ml of water to dissolve the residue. The organic layer wasseparated, 40 ml of water was again added, and the pH was adjusted to1.5 with 2N hydrochloric acid with ice-cooling. Then, the organic layerwas separated, and 40 ml of water was added, after which the pH wasadjusted to 7.0 with sodium hydrogen carbonate with ice-cooling. Theorganic layer was separated and dried on anhydrous magnesium sulfate,after which the solvent was removed by distillation under reducedpressure. Diethyl ether was added to the residue, and the resultingcrystals were collected by filtration, to obtain 7.06 g (yield 93.0%) ofdiphenylmethyl7-[2-(2-tert.amyloxycarboxamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]Δ³-cephem-4-carboxylate having a melting point of 94°-99° C. (decomp ).

IR(KBr) cm⁻¹ : 1790, 1725, 1685.

NMR(d₆ -DMSO) ppm value: 0.87 (3H, t, J=7 Hz, --CH₂ CH₃), 1.44##STR315## 1.75 (2H, q, J=7 Hz, --CH₂ CH₃), 2.4 ##STR316## 3.46 (2H, bs,C₂ -H), 3.81 (3H, s, --OCH₃), 5.15 (1H, d, J=5 Hz, C₆ -H), 5.47##STR317## 5.86 (1H, dd, J=5 Hz, J=8 Hz, C₇ -H), 6.84 (1H, s, >CH--),6.93-7.52 ##STR318## 9.61 (1H, d, J=8 Hz, --CONH--), 11.66 (1H, bs,--CONH--).

(2) The compound obtained in above (1) was subjected to reaction andtreatment in the same manner as in Example 8-(2) to obtain the followingcompound: 5.07 g (yield 91.9%) of trifluoroacetic acid salt of7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylic acid

Melting point: 123°-125° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1790, 1720-1635.

NMR(CD₃ OD) ppm value: 2.45 ##STR319## 3.44 (2H, bs, C₂ -H), 3.99 (3H,s, --OCH₃), 5.10 (1H, d, J=5 Hz, C₆ -H), 5.50, 5.81 ##STR320## 5.80 (1H,d, J=5 Hz, C₇ -H), 6.93 ##STR321##

(3) The compound obtained in above (2) was subjected to reaction andtreatment in the same manner as in Example 8-(3) to obtain the followingcompound: Sodium7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)-methyl]-Δ³-cephem-4-carboxylate

Melting point: 183°-187° C. (decomp.).

IR(KBr) cm⁻¹ : 1760, 1665, 1610.

NMR(d₆ -DMSO-D₂ O) ppm value: 2.50 ##STR322## 3.30 (2H, bs, C₂ -H), 3.91(3H, s, --OCH₃), 5.12 (1H, d, J=5 Hz, C₆ -H), 5.66 ##STR323## 5.74 (1H,d, J=5 Hz, C₇ -H), 6.83 ##STR324##

The following compound was obtained by the same manner.

Sodium7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[(-3-chloro-1,2,4-triazolyl)methyl]-Δ³-cephem-4-carboxylate

Melting point: 168° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1760, 1670, 1605.

NMR(D₂ O) ppm value: 3.30 (2H, bs, C₂ -H), 3.97 (3H, s, --OCH₃),4.93-5.60 ##STR325## 5,77 (1H, d, J=5 Hz, C₇ -H), 6.91 ##STR326## 7.96##STR327##

EXAMPLE 19

In 25 ml of water was suspended 6.13 g of trifluoroacetic acid salt of7-[2-(2-aminothiazol-4yl)-2-(syn)-methoxyiminoacetamido]-3-[(3-chloro-1,2,4-triazolyl)methyl]-.DELTA.³-cephem-4-carboxylic acid, and to the suspension was added sodiumhydrogen carbonate with ice-cooling to adjust the pH of the suspensionto 8.0, upon which the suspension was converted to a solultion. Then,the pH was adjusted to 2.5 with concentrated hydrocholoric acid at thesame temperature as above, upon whichg crystals were deposited. Thecrystals were collected by filtration, thoroughly washed with water andthen with acetone, and dried, to obtain 4.71 g (yield 94.5%) of7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[(3-chloro-1,2,4-triazolyl)methyl]-Δ³-cephem-4-carboxylic acid having a melting point of at least 200° C.

IR(KBr) cm⁻¹ : ν_(C)═O 1765, 1660, 1625.

NMR(d₆ -DMSO) ppm value: 3.44 (2H, bs, C₂ -H), 3.85 (3H, s, --OCH₃),5.20 ##STR328## 5.20 (1H, d, J=6 Hz, C₆ -H), 5.78 (1H, dd, J=6 Hz, J=8Hz, C₇ -H), 6.71 ##STR329## 7.16 (2H, bs, --NH₂), 8.04 ##STR330## 9.60(1H, d, J=8 Hz, --CONH--).

In the same manner as above, the following compound was obtained:

7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylic acid

Melting point: >200° C.

IR(KBr) cm⁻¹ : ν_(C)═O 1756, 1660, 1625.

EXAMPLE 20

By carrying out an acylation reaction in the same manner as in Example17-(1) or Example 18-(1), the compounds shown in Table 16 were obtained.

                                      TABLE 16                                    __________________________________________________________________________     ##STR331##                                                                                                      Melting                                                                       point IR(KBr)                              R.sup.1     R.sup.2    R.sup.5     (°C.)                                                                        cm.sup.-1 : ν.sub.C═O         __________________________________________________________________________                 ##STR332##                                                                               ##STR333## 180-183 (decomp.)                                                                   1780, 1710, 1670                     H           NHCOCH.sub.3                                                                             ClCH.sub.2 CONH                                                                           >200                                                                                 ##STR334##                          H                                                                                          ##STR335##                                                                              ClCH.sub.2 CONH                                                                           147-150 (decomp.)                                                                    ##STR336##                           ##STR337##                                                                                ##STR338##                                                                               ##STR339## 104-109 (decomp.)                                                                   1780, 1720, 1680                      ##STR340##                                                                                ##STR341##                                                                               ##STR342## 130-132 (decomp.)                                                                   1780, 1720, 1680                     "           NHCOCH.sub.3                                                                             "           163 (decomp.)                                                                        ##STR343##                          "                                                                                          ##STR344##                                                                              "           165-166 (decomp.)                                                                    ##STR345##                          "                                                                                          ##STR346##                                                                              "            98-105 (decomp.)                                                                   1780, 1723, 1680                     "                                                                                          ##STR347##                                                                              "            94-101 (decomp.)                                                                   1775, 1720, 1670                      ##STR348##                                                                                ##STR349##                                                                              ClCH.sub.2 CONH                                                                           156-157 (decomp.)                                                                   1780, 1745, 1680, 1655               __________________________________________________________________________

EXAMPLE 21

By carrying out the reaction and treatment in the same manner as inExample 17 or Example 18, the compounds shown in Table 17 and Table 18were obtained.

                                      TABLE 17                                    __________________________________________________________________________     ##STR350##                                                                                Melting                                                                             IR(KBr)                                                    Compound     point cm.sup.-1 :                                                R.sup.2      (°C.)                                                                        ν.sub.C=0                                                                       NMR(d.sub.6 -DMSO) ppm value:                         __________________________________________________________________________     ##STR351##  153-159 (decomp.)                                                                   1775, 1670, 1630                                                                    ##STR352##                                                                   d, J=8Hz, CONH)                                        ##STR353##  156-159 (decomp.)                                                                   1765, 1700, 1665, 1630                                                              ##STR354##                                                                   9.05 (1H, d, J=8Hz, CONH), 11.02 (1H, s, CONH)         ##STR355##  135 (decomp.)                                                                       1770, 1705, 1665, 1630                                                              ##STR356##                                                                    ##STR357##                                                                    ##STR358##                                            ##STR359##  142 (decomp.)                                                                       1775, 1660, 1630                                                                    ##STR360##                                                                    ##STR361##                                                                   J=7Hz, CONH)                                           ##STR362##  150 (decomp.)                                                                       1775, 1660, 1630                                                                    ##STR363##                                                                    ##STR364##                                                                   J=8Hz, CONH)                                           ##STR365##  121-125 (decomp.)                                                                   1775 1670 1630                                                                      ##STR366##                                                                   CONH)                                                  ##STR367##  181 (decomp.)                                                                       1775, 1710, 1665, 1630                                                              ##STR368##                                                                    ##STR369##                                                                   CONH)                                                  ##STR370##  168-180 (decomp.)                                                                    ##STR371##                                                                         ##STR372##                                                                    ##STR373##                                                                   J=8Hz, CONH)                                           ##STR374##  141-144 (decomp.)                                                                   1778, 1710, 1670 1630                                                               ##STR375##                                                                    ##STR376##                                                                    ##STR377##                                            ##STR378##  183 (decomp.)                                                                        ##STR379##                                                                         ##STR380##                                                                    ##STR381##                                                                    ##STR382##                                                                    ##STR383##                                                                   d, J=8Hz, CONH)                                       NHCOCH.sub.3 166   1775,                                                                              1.85 (3H, s, COCH.sub.3), 3.42 (2H, bs,                                       C.sub.2H), 3.86                                                    (decomp.)                                                                            ##STR384##                                                                         ##STR385##                                                                    ##STR386##                                                                   (1H, m, NHCO), 9.64 (1H, d, J=8Hz, CONH)               ##STR387##   137-141 (decomp.)                                                                  1760, 1660, 1630                                                                    ##STR388##                                                                    ##STR389##                                            ##STR390##  155-159 (decomp.)                                                                    ##STR391##                                                                         ##STR392##                                                                    ##STR393##                                                                   9.57 (1H, d, J=8Hz, CONH)                              ##STR394##  165 (decomp.)                                                                        ##STR395##                                                                         ##STR396##                                                                    ##STR397##                                                                   J=8Hz, CONH)                                          __________________________________________________________________________

                                      TABLE 18                                    __________________________________________________________________________     ##STR398##                                                                                  IR(KBr)               IR(KBr)                                  R.sup.2        cm.sup.-1 : ν.sub.C═O                                                         R.sup.2        cm.sup.-1 : ν.sub.C═O             __________________________________________________________________________     ##STR399##    1770, 1665, 1630                                                                      ##STR400##    1770, 1665, 1630                          ##STR401##    1770,  1730, 1665, 1630                                                               ##STR402##    1775, 1660, 1630                          ##STR403##    1770, 1665, 1630                                                                      ##STR404##    1775, 1665, 1630                          ##STR405##    1770, 1730, 1670, 1630                                                                ##STR406##    1775, 1670, 1630                          ##STR407##    1775, 1740, 1670, 1630                                                                ##STR408##                                                                                   ##STR409##                               ##STR410##    1775, 1725, 1660, 1630                                                                ##STR411##                                                                                   ##STR412##                               ##STR413##    1775, 1730, 1665, 1630                                                                ##STR414##                                                                                   ##STR415##                              __________________________________________________________________________

EXAMPLE 22

(1) In 25 ml of anhydrous methylene chloride was dissolved 2.2 g ofdiketene and a solution of 1.85 g of chlorine in 20 ml of anhydrouscarbon tetrachloride was dropped into the resulting solution at -30° C.The resulting solution was subjected to reaction at -30° C. to -20° C.for 30 minutes. The reaction was dropped at a temperature of -30° C. orbelow into a solution of 9.63 g of diphenylmethyl7-amino-3-[(3-chloro-1,2,4-triazolyl)methyl]-Δ³ -cephem-4-carboxylateand 4 g of bis(trimethylsilyl)acetamide in 100 ml of anhydrous methylenechloride, after which the mixture was subjected to reaction at -30° C.to -20° C. for 30 minutes and then at 0°-10° C. for 1 hour. Aftercompletion of the reaction, the solvent was removed by distillationunder reduced pressure, and the residue obtained was dissolved in 100 mlof ethyl acetate and 80 ml of water. The organic layer was separated,washed successively with 50 ml of water and 50 ml of saturated aqueoussolution of sodium chloride and dried on anhydrous magnesium sulfate,after which the solvent was removed by distillation under reducedpressure. Diisopropyl ether was added to the residue, and the resultingcrystals were collected by filtration to obtain 10.7 g (yield 89.2%) ofdiphenylmethyl7-(4-chloro-3-oxobutyramido)-3-[(3-chloro-1,2,4-triazolyl)-methyl]-Δ³-cephem-4-carboxylate having a melting point of 73°-75° C.

IR(KBr) cm⁻¹ : ν_(C)═O 1780, 1725, 1690-1650.

NMR(CDCl₃ -D₂ O) ppm value: 3.19 (2H, bs, C₂ -H), 3.50 (2H, s, --COCH₂CO--), 4.12 (2H, s, ClCH₂ --, 4.88 (1H, d, J=5 Hz, C₆ -H), 4.82, 5.35##STR416## 5.72 (1H, d, J=5 Hz, C₇ -H), 6.90 (1H, s, >CH--), 7.26##STR417## 7.71 ##STR418##

(2) In 40 ml of acetic acid was dissolved 6 g of diphenylmethyl7-(4-chloro-3-oxobutyramido)-3-[(3-chloro-1,2,4-triazolyl)methyl]-Δ.sup.3-cephem-4-carboxylate, and a solution of 1 g of sodium nitrite in 6 mlof water was dropped into the resulting solution over a period of 1 hourwith ice-cooling. Then, the mixture was subjected to reaction at roomtemperature for 2 hours. After completion of the reaction, the reactionmixture was introduced into 600 ml of water to deposit crystals, whichwere collected by filtration, thoroughly washed with water and dried, toobtain 5.24 g (yield 83.3%) of diphenylmethyl7-(4-chloro-2-hydroxyimino-3-oxobutyramido)-3-[(3-chloro-1,2,4-triazolyl)methyl]-Δ³-cephem-4-carboxylate having a melting point of 93°-95° C. (decomp.).

IR(KBr) cm⁻¹ : 1780, 1720, 1700-1650.

NMR(CDCl₃ -D₂ O) ppm value: 3.20 (2H, bs, C₂ -H), 4.59 (2H, s, ClCH₂--), 4.93 (1H, d, J=5 Hz, C₆ -H), 4.79, 5.16 ##STR419## 5.78 (1H, d, J=5Hz, C₇ -H), 6.90 (1H, s, >CH--), 7.24 ##STR420## 7.71 ##STR421##

(3) In 35 ml of N,N-dimethylformamide was dissolved 6.29 g ofdiphenylmethyl7-(4-chloro-2-hydroxyimino-3-oxobutyramido)-3[(3-chloro-1,2,4-triazolyl)methyl]-Δ³-cephem-4-carboxylate. While cooling the solution with ice, 1.5 g ofsodium carbonate and 2.1 g of dimethyl sulfate were added thereto, andthen the mixture was subjected to reaction at 5°-10° C. for 1 hour.After completion of the reaction, the reaction mixture was introducedinto 600 ml of water to deposit crystals, which were collected byfiltration and purified by a column chromatography (Wako silica gelC-200; developing solvent, benzene:ethyl acetate=9:1), to obtain 2.7 g(yield 42%) of diphenylmethyl7-(4-chloro-2-(syn)methoxyimino-3-oxobutyramido)-3-[(3-chloro-1,2,4-triazolyl)methyl]-Δ³-cephem-4-carboxylate having a melting point of 102°-104° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1782, 1720, 1690, 1670. NMR(CDCl₃ -D₂ O) ppmvalue: 3.20 (2H, bs, C₂ -H), 4.05 (3H, s, --OCH₃), 4.50 (2H, s, ClCH₂--), 4.95 (1H, d, J=5 Hz, C₆ -H), 4.82, 5.36 ##STR422## 5.85 (1H, d, J=5Hz, C₇ -H), 6.95 (1H, s, >CH--), 7.35 ##STR423## 7.72 ##STR424##

(4) In 48 ml of N,N-dimethylacetamide were dissolved 6.43 g ofdiphenylmethyl7-(4-chloro-2-(syn)methoxyimino-3-oxobutyramido)-3-[(3-chloro-1,2,4-triazolyl)methyl]-Δ³-cephem-4-carboxylate and 1 g of thiourea, and the resulting solutionwas subjected to reaction at room temperature for 2 hours. Aftercompletion of the reaction, the reaction mixture was introduced into amixed solvent of 600 ml of water and 600 ml of ethyl acetate. Then, thepH thereof was adjusted to 6.7 with sodium hydrogen carbonate, and theorganic layer was separated. The aqueous layer was additionallyextracted with two portions of 300 ml of ethyl acetate. The organiclayer were combined, washed with two portions of 800 ml of water anddried on anhydrous magnesium sulfate, after which the solvent wasremoved by distillation under reduced pressure. Diethyl ether was addedto the residue, and the resulting crystals were collected by filtration,to obtain 5.87 g (yield 88%) of diphenylmethyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3[(3-chloro-1,2,4-triazolyl)methyl]-.DELTA.³-cephem-4-carboxylate having a melting point of 155°-157° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1781, 1725, 1672.

NMR(CDCl₃ -D₂ O) ppm value: 3.20 (2H, bs, C₂ -H), 3.86 (3H, s, --OCH₃),4.99 (1H, d, J=5 Hz, C₆ -H), 4.82, 5.41 ##STR425## 5.96 (1H, d, J=5 Hz,C₇ -H), 6.62 ##STR426## 6.92 (1H, s, >CH--), 7.28 ##STR427## 7.71##STR428##

(5) In a mixed solvent of 35 ml of trifluoroacetic acid and 10 ml ofanisole was dissolved 6.65 g of diphenylmethyl7-[2-(2-aminothiazol-4-yl)-2-(syn)methoxyiminoacetamido]-3-[(3-chloro-1,2,4-triazolyl)methyl]-Δ³-cephem-4-carboxylate, and the resulting solution was subjected toreaction at room temperature for 1 hour. After completion of thereaction, the solvent was removed by distillation under reducedpressure, and diethyl ether was added to the residue, after which theresulting crystals were collected by filtration, thoroughly washed withdiethyl ether and dried to obtain 5.71 g (yield 93.2%) oftrifluoroacetic acid salt of7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-(3-chloro-1,2,4-triazolyl)methyl-Δ³-cephem-4-carboxylic acid having a melting point of 162° C. (decomp.).

The physical properties (IR and NMR data) of this compound wereidentical with those of the product obtained in Example 17-(2).

EXAMPLE 23

In 50 ml of anhydrous tetrahydrofuran were dissolved 2.24 g of4-bromo-3-oxo-2-methoxyiminobutyric acid, 2.0 g of 1-oxybenztriazole and4.62 g of diphenylmethyl 7-amino-3-[(3-chloro-1,2,4-triazolyl)methyl]-Δ³-cephem-4-carboxylate, and the solution was cooled to 5° C. Then, 2.5 gof N,N'-dicyclohexylcarbodiimide was added, and the resulting mixturewas subjected to reaction at the same temperature for 30 minutes andthen at room temperature for 5 hours. After completion of the reaction,the insoluble matter was removed by filtration and the solvent wasremoved from the filtrate by distillation under reduced pressure. To theresidue was added 40 ml of ethyl acetate, and a small quantity ofinsoluble matter was removed by filtration, after which the ethylacetate solution was washed successively with 5% by weight aqueoussolution of sodium hydrogen carbonate and water, and dried on anhydrousmagnesium sulfate. The solvent was then removed by distillation underreduced pressure. The residue thus obtained was purified by a columnchromatography (Wako silica gel C-200; developing solvent, benzene:ethylacetate=9:1) to obtain 3.65 g (yield 54.6%) of diphenylmethyl7-(4-bromo-2-methoxyimino-3-oxobutyramido)-3-(3-chloro-1,2,4-triazolyl)methyl-Δ³-cephem-4-carboxylate having a melting point of 91°-94° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1780, 1720, 1680.

NMR(d₆ -DMSO) ppm value: 3.55 (2H, bs, C₂ -H), 3.84 (3H, s, --OCH₃),4.16 (2H, s, BrCH₂ --), 4.99-5.53 ##STR429## 5.87 (1H, dd, J=5 Hz, J=8Hz, C₇ -H), 7.06 (1H, s, >CH--), 7.40 ##STR430## 8.04 ##STR431## 10.01(1H, d, J=8 Hz, --CONH--).

In the same manner as above, the following compound was obtained:

Diphenylmethyl7-(4-bromo-2-methoxyimino-3-oxobutyramido)-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³ -cephem-4-carboxylate

Melting point: 80°-82° C. (decomp.)

IR(KBr) cm⁻¹ : ν_(C)═O 1780, 1720, 1680.

NMR(CDCl₃) ppm value: 2.41 ##STR432## 3.16 (2H, bs, C₂ -H), 4.00 (3H, s,--OCH₃), 4.25 (2H, s, BrCH₂ --), 4.88 (1H, d, J=5 Hz, C₆ -H), 5.38##STR433## 5.78 (1H, dd, J=5 Hz, J=8 Hz, C₇ -H), 6.81 (1H, s, >CH--),7.18 ##STR434## 9.10 (1H, d, J=8 Hz, --CONH--).

EXAMPLE 24

In 50 ml of anhydrous tetrahydrofuran were dissolved 1.45 g of3-oxo-2-methoxyiminobutyric acid, 2.0 g of 1-oxybenztriazole and 4.62 gof diphenylmethyl 7-amino-3-[(3-chloro-1,2,4-triazolyl)methyl]-Δ³-cephem-4-carboxylate and the solution was cooled to 5° C. Then, 2.5 gof N,N'-dicyclohexylcarbodiimide was added thereto and the resultingmixture was subjected to reaction at the same temperature for 30 minutesand then at room temperature for 5 hours. After completion of thereaction, the insoluble matter was removed by filtration, and thesolvent was removed from the filtrate by distillation under reducedpressure. To the residue was added 40 ml of ethyl acetate, and a smallquantity of insoluble matter was removed by filtration, after which thefiltrate was washed successively with 5% by weight aqueous solution ofsodium hydrogen carbonate and water, and dried on anhydrous magnesiumsulfate. The solvent was removed by distillation under reduced pressure.The residue thus obtained was purified by a column chromatography (Wakosilica gel C-200; developing solvent, benzene:ethyl acetate=8:1) toobtain 3.7 g (yield 62.8%) of diphenylmethyl7-(2-methoxyimino-3-oxobutyramido)-3-[(3-chloro-1,2,4-triazolyl)methyl]-.DELTA.³-cephem-4-carboxylate having a melting point of 102°-103° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1775, 1740, 1670. NMR(d₆ -DMSO) ppm value: 2.31(3H, s, --COCH₃), 3.47 (2H, bs, C₂ -H), 4.00 (3H, s, --OCH₃), 4.90-5.40##STR435## 5.89 (1H, dd, J=8 Hz, J=5 Hz, C₇ -H), 6.93 (1H, s, --CH<),7.30 ##STR436## 7.95 ##STR437## 9.43 (1H, d, J=8 Hz, --CONH--).

In the same manner as above, the following compound was obtained:

Diphenylmethyl 7-(2-methoxyimino-3-oxobutyramido)-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³ -cephem-4-carboxylate.

Melting point: 88°-90° C. (decomp.). IR(KBr) cm⁻¹ : ν_(C)═O 1775, 1720,1685, 1670.

NMR(d₆ -DMSO) ppm value: 2.27 (3H, s, --COCH₃), 2.37 ##STR438## 3.46(2H, bs, C₂ -H), 3.93 (3H, s, --OCH₃), 5.10 (2H, d, J=5 Hz, C₆ -H), 5.42##STR439## 5.82 (1H, dd, J=5 Hz, J=8 Hz, C₇ -H), 6.82 (1H, s, >CH--),7.17 ##STR440## 9.27 (1H, d, J=8 Hz, --CONH--).

EXAMPLE 25

(1) In 90 ml of anhydrous methylene chloride was suspended 2.96 g of7-amino-3-[(3-chloro-1,2,4-trizaolyl)methyl]-Δ³ -cephem-4-carboxylicacid and 2.02 g of triethylamine and 1.7 of diketene were added to thesuspension with ice-cooling, after which the mixture was subjected toreaction at 5°-10° C. for 4 hours. After completion of the reaction, 100ml of water was added to the reaction mixture, and the aqueous layer wasseparated. Then, 100 ml of ethyl acetate was added to the aqueous layer,and the pH thereof was adjusted to 1.0 with 2N hydrochloric acid. Afterremoving a slight quantity of insoluble matter, the organic layer wasseparated and dried on anhydrous magnesium sulfate. With stirring, about1.6 g of diphenyldiazomethane was slowly added thereto and the resultingmixture was subjected to reaction for about 30 minutes. After completionof the reaction, the solvent was removed by distillation under reducedpressure. Isopropyl ether was added to the residue, and the resultingcrystals were collected by filtration, thoroughly washed with isopropylether and then dried to obtain 3.3 g (yield 60.4%) of diphenylmethyl7-(3-oxobutyramido)-3-[(3-chloro-1,2,4-triazolyl)methyl]-Δ³-cephem-4-carboxylate having a melting point of 75°-77 ° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1775, 1720, 1670.

NMR(d₆ -DMSO) ppm value: 2.17 (3H, s, --COCH₃), 3.48 (4H, bs, C₂ -H,--COCH₂ CO--), 5.00-5.40 ##STR441## 5.86 (1H, dd, J=8 Hz, J=5 Hz, C₇-H), 6.99 (1H, s, --CH<), 7.36 ##STR442## 8.03 ##STR443## 9.12 (1H, d,J=8 Hz, --CONH--).

In the same manner as above, the following compound was obtained:

Diphenylmethyl7-(3-oxobutyramido)-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ.sup.3-cephem-4-carboxylate.

Melting point: 84°-86° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1780, 1720, 1670.

NMR(d₆ -DMSO) ppm value: 2.06 (3H, s, --COCH ), 2.31 ##STR444## 3.34(2H, s, --COCH₂ CO--), 3.46 (2H, bs, C₂ -H), 5.00 (1H, d, J=5 Hz, C₆-H), 5.31 ##STR445## 5.63 (1H, dd, J=5 Hz, J=8 Hz, C₇ -H), 6.71 (1H,s, >CH--), 7.06 ##STR446## 8.75 (1H, d, J=8 Hz, --CONH--).

(3) The diphenylmethyl7-(3-oxobutyramido)-3-[(3-chloro-1,2,4-triazolyl)methyl]-Δ³-cephem-4-carboxylate obtained in above (1) was subjected to reactionand treatment in the same manner as in Example 22-(2) to obtaindiphenylmethyl7-(2-hydroxyimino-3-oxobutyramido)-[3-(3-chloro-1,2,4-triazolyl)methyl]-.DELTA.³-cephem-4-carboxylate having a melting point of 108°-110° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1780, 1720, 1680.

NMR(d₆ -DMSO) ppm value: 2.32 (3H, s, --COCH₃), 3.44 (2H, bs, C₂ -H),4.90-5.40 ##STR447## 5.88 (1H, dd, J=8 Hz, J=5 Hz, C₇ -H), 6.94 (1H, s,--CH<), 7.33 ##STR448## 8.00 ##STR449## 9.30 (1H, d, J=8 Hz, --CONH--),12.82 (1H, s, ═N--OH).

In the same manner as above, the following compound was obtained:

Diphenylmethyl7-(2-hydroxyimino-3-oxobutyramido)-3[-2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate.

Melting point: 102°-105° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1780, 1720, 1680.

NMR(d₆ -DMSO) ppm value: 2.25 (3H, s, --COCH₃), 2.35 ##STR450## 3.44(2H, bs, C₂ -H), 5.05 (1H, d, J=5 Hz, C₆ -H), 5.37 ##STR451## 5.76 (1H,dd, J=5 Hz, J=8 Hz, C₇ -H), 6.71 (1H, s, >CH--), 7.11 ##STR452## 9.04(1H, d, J=8 Hz, --CONH--).

(3) The diphenylmethyl7-(2-hydroxyimino-3-oxobutyramido)-3-[(3-chloro-1,2,4-triazolyl)methyl]-.DELTA.³-cephem-4-carboxylate and diphenylmethyl7-(2-hydroxyimino-3-oxobutyramido)-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³ -cephem-4-carboxylate obtained in above (2) was subjected toreaction and treatment in the same manner as in Example 22-(3) to obtaindiphenylmethyl7-(2-methoxyimino-3-oxobutyramido)-3-[(3-chloro-1,2,4-triazolyl)methyl]-.DELTA.³-cephem-4-carboxylate having a melting point of 102°-103° C. (decomp.)and diphenylmethyl7-(2-methoxyimino-3-oxobutyramido)-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate having a melting point of 88°-90° C. (decomp.).

The physical properties (IR and NMR) of these compounds were identicalwith those of the compounds obtained in Example 24.

EXAMPLE 26

In 120 ml of dry tetrahydrofuran was dissolved 5.89 g of diphenylmethyl7-(2-methoxyimino-3-oxobutyramido)-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate, and thereto was added 1.34 g of alumimumchloride. To the solution was added to 5.00 g of pyridinium hydrobromideperbromide at room temperature, and the resulting mixture was stirred atsaid temperature for 30 minutes. After completion of the reaction, thesolvent was removed by distillation under reduced pressure, and to theresidue were added 50 ml of ethyl acetate and 50 ml of water. A smallamount of insoluble matter was removed by filtration, and the organiclayer was separated, washed with water, and dried on anhydrous magnesiumsulfate, after which the solvent was removed by distillation underreduced pressure. The residue thus obtained was purified by a columnchromatography (Wako silica gel C-200; developing solvent, benzene:ethylacetate=9:1), to obtain 4.13 g (yield 61.8%) of diphenylmethyl7-[4-bromo-2-methoxyimino-3-oxobutyramido]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate having a melting point of 80°-82° C. (decomp.).

EXAMPLE 27

By subjecting various starting compounds to the same reaction as inExample 22, the corresponding objective compounds shown in Table 19 wereobtained.

The physical properties of these compounds were identical with those ofthe compounds produced in Example 21.

                                      TABLE 19                                    __________________________________________________________________________     ##STR453##                                                                   R.sup.2        R.sup.2        R.sup.2                                         __________________________________________________________________________     ##STR454##                                                                                   ##STR455##                                                                                   ##STR456##                                      ##STR457##                                                                                   ##STR458##                                                                                   ##STR459##                                      ##STR460##                                                                                   ##STR461##                                                                                   ##STR462##                                      ##STR463##                                                                                   ##STR464##                                                                                   ##STR465##                                     NHCOCH.sub.3                                                                                  ##STR466##                                                                                   ##STR467##                                      ##STR468##                                                                                   ##STR469##                                                                                   ##STR470##                                      ##STR471##                                                                                   ##STR472##                                                     ##STR473##                                                                                   ##STR474##                                                     ##STR475##                                                                                   ##STR476##                                                     ##STR477##                                                                                   ##STR478##                                                     ##STR479##                                                                                   ##STR480##                                                    __________________________________________________________________________

EXAMPLE 28

(1) In 40 ml of acetic acid was dissolved 6.25 g of diphenylmethyl7-(4-bromo-3-oxobutyramido)-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-.DELTA.³-cephem-4-carboxylate obtained in Example 12-(1), and to the solutionwas dropwise added a solution of 1 g of sodium nitrite in 6 ml of waterwith ice-cooling over a period of 1 hour. Then, the mixture wassubjected to reaction at room temperature for 2 hours. After completionof the reaction, the reaction mixture was introduced into 600 ml ofwater to deposit crystals, which were collected by filtration,thoroughly washed with water and dried to obtain 5.43 g (yield 83.0%) ofdiphenylmethyl7-(4-bromo-2-hydroxyimino-3-oxobutyramido)-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate having a melting point of 97°-100° C.

IR(KBr) cm⁻¹ : ν_(C)═O 1780, 1720, 1695-1650.

NMR(CDCl₃) ppm value: 2.49 ##STR481## 3.23 (2H, s, C₂ -H), 4.42 (2H, s,BrCH₂ -), 4.92 (1H, d, J=5 Hz, C₆ -H), 5.32, 5.70 ##STR482## 5.78 (1H,d, J=5 Hz, C₇ -H), 6.89 (1H, s, >CH--), 7.23 ##STR483## 9.10 (1H, d, J=8Hz, --CONH--).

(2) In 35 ml of N,N-dimethylacetamide were dissolved 6.54 g ofdiphenylmethyl 7-(4-bromo-2-hydroxyimino-3-oxobutyramido)-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³ -cephem-4-carboxylate and 1g of thiourea, and the solution was subjected to reaction at roomtemperature for 2 hours. After completion of the reaction, the reactionmixture was introduced into a mixed solvent of 500 ml of water and 500ml of ethyl acetate. Then, the pH of the mixture was adjusted to 7.0with sodium carbonate, and the organic layer was separated. The aqueouslayer was additionally extracted with two portions of 200 ml of ethylacetate. The organic layers were combined and dried on anhydrousmagnesium sulfate, after which the solvent was removed by distillationunder reduced pressure. The residue was purified by a columnchromatography (Wako silica gel C-200; developing solvent,chloroform:methanol=20:1) to obtain 3.2 g (yield 50.7%) ofdiphenylmethyl7-[2-(2-aminothiazol-4-yl)-2-(syn)-hydroxyiminoacetamido]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate having a melting point of 164° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1780, 1730, 1670.

NMR(d₆ DMSO) ppm value:

2.40 ##STR484## 3.41 (2H, bs, C₂ -H), 5.14 (1H, d, J=5 Hz, C₆ -H),5.20-6.10 ##STR485## 6.63 ##STR486## 6.90 (1H, s, >CH--), 7.28##STR487## 9.46 (1H, d, J=8 Hz, --CONH--).

(3) In a mixed solvent of 32 ml of trifluoroacetic acid and 10 ml ofanisole was dissolved 6.31 g of diphenylmethyl7-[2-(2-aminothiazol-4-yl)-2-(syn)-hydroxyiminoacetamido]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate, and the solution was subjected to reaction atroom temperature for 1.5 hours. After completion of the reaction, thesolvent was removed by distillation under reduced pressure, and diethylether was added to the residue. The resulting crystals were collected byfiltration, thoroughly washed with diethyl ether and dried to obtain5.33 g (yield 92.1%) of trifluoroacetic acid salt of7-[2-(2-aminothiazol-4-yl)-2-(syn)-hydroxyiminoacetamido]-3-[2-(5-methyl-1,2,3,4tetrazolyl)methyl]-Δ³-cephem-4-carboxylic acid having a melting point of 175° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1770, 1680-1630.

NMR(d₆ -DMSO) ppm value: 2.43 ##STR488## 3.41 (2H, bs, C₂ -H), 5.13 (1H,d, J=5 Hz, C₆ -H), 5.26-5.95 ##STR489## 6.67 ##STR490## 9.48 (1H, d, J=8Hz, --CONH--).

In the same manner as above, the following compounds were obtained:

Trifluoroacetic acid salt of7-[2-(2-aminothiazol-4-yl)-2-(syn)-hydroxyiminoacetamido]-3-benzyl-Δ³-cephem-4-carboxylic acid

Melting point: 139° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1760, 1710, 1660.

NMR(d₆ -DMSO) ppm value: 3.40 (2H, bs, C₂ -H), 3.89 ##STR491## 5.18 (1H,d, J=4 Hz, C₆ -H), 5.50-5.84 (1H, m, C₇ -H), 6.89 ##STR492## 7.25##STR493## 8.20-9.95 (4H, m, --N.sup.⊕ H₃, --CONH--).

Trifluoroacetic acid salt of7-[2-(2-aminothiazol-4-yl)-2-(syn)-hydroxyiminoacetamido]-3-acetamidomethyl-Δ³-cephem-4-carboxylic acid

IR(KBr) cm⁻¹ : ν_(C)═O 1775, 1710-1620.

(4) The trifluoroacetic acid salt of7-[2-(2-aminothiazol-4-yl)-2-(syn)-hydroxyiminoacetamido]-3-acetamidomethyl-Δ³-cephem-4-carboxylic acid obtained in above (3) was subjected toreaction and treatment in the same manner as in Example 8-(3) to obtainthe following compound:

Sodium7-[2-(2-aminothiazol-4-yl)-2-(syn)-hydroxyiminoacetamido]-3-acetamidomethyl-Δ³-cephem-4-carboxylate

Melting point: >200° C.

IR(KBr) cm⁻¹ : ν_(C)═O 1750, 1680, 1665, 1605.

NMR(D₂ O) ppm value: 1.98 (3H, s --COCH₃),3.29 , 3.62 (2H, ABq, J=18 Hz,C₂ -H), 3.86, 4.20 ##STR494## 5.11 (1H, d, J=5 Hz, C₆ -H, 5.76 (1H, d,J=5 Hz, C₇ -H), 6.84 ##STR495##

EXAMPLE 29

(1) In 13 ml of N,N-dimethylacetamide was dissolved 2.49 g of2-(2-chloroacetamidothiazol-4-yl)glyoxylic acid, and to the solution wasdropwise added 3.07 g of phosphorus oxychloride at -20° C. The resultingmixture was subjected to reaction at -20° C. to -10° C. for 1 hour, and4.62 g of diphenylmethyl7-amino-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate was added. The resulting mixture was subjected toreaction at -20° C. to -10° C. for 30 minutes and then at roomtemperature for 30 minutes. After completion of the reaction, thereaction mixture was introduced into a mixed solvent of 40 ml of waterand 60 ml of ethyl acetate. Then, the pH thereof was adjusted to 7.0with sodium hydrogen carbonate, and the organic layer was separated,washed with 30 ml of water and dried on anhydrous magnesium sulfate. Thesolvent was removed by distillation under reduced pressure, and diethylether was added to the resulting residue, after which the resultingcrystals were collected by filtration, to obtain 6.35 g (yield 91.6%) ofdiphenylmethyl7-[2-(2-chloroacetamidothiazol-4-yl)glyoxylamido]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate having a melting point of 115°-119° C.

IR(KBr) cm⁻¹ : ν_(C)═O 1780, 1720, 1670.

NMR(d₆ -DMSO) ppm value: 2.46 (3H, s, --CH₃), 3.62 (2H, bs, C₂ -H), 4.47(2H, s, ClCH₂ --), 5.37 (1H, d, J=5 Hz, C₆ -H), 5.63 ##STR496## 6.06(1H, dd, J=5 Hz, J=8 Hz, C₇ -H), 7.07 (1H, s, >CH--), 7.41 ##STR497##8.52 ##STR498## 10.07 (1H, d, J=8 Hz, --CONH--).

In the same manner as above, the following compound was obtained:

Diphenylmethyl7-[2-(2-chloroacetamidothiazol-4-yl)glyoxylamido]-3-[(3-chloro-1,2,4-triazolyl)methyl]-Δ³-cephem-4-carboxylate

Melting point: 121°-123° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1775, 1720, 1663.

NMR(d₆ -DMSO) ppm value: 3.52 (2H, bs, C₂ -H), 4.43 (2H, s, ClCH₂ --),4.94-5.57 ##STR499## 5.98 (1H, dd, J=5 Hz J=8 Hz, C₇ -H), 7.00 (1H,s, >CH--), 7.07-7.67 ##STR500## 7.99 ##STR501## 8.42 ##STR502## 9.93(1H, d, J=8 Hz, --CONH--).

(2) In 30 ml of methanol was dissolved 0.84 g of methoxyaminehydrochloride, and 0.76 g of triethylamine was added thereto, afterwhich 3.46 g of the diphenylmethyl7-[2-(2-chloroacetamidothiazol-4-yl)-glyoxylamido]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate obtained in above (1) was added thereto. Theresulting mixture was subjected to reaction at room temperature for 3hours. After completion of the reaction, the solvent was removed bydistillation under reduced pressure, and 30 ml of water and 30 ml ofethyl acetate were added to the residue, after which the organic layerwas separated, washed with 20 ml of water and dried on anhydrousmagnesium sulfate. The solvent was then removed by distillation underreduced pressure. Diethyl ether was added to the residue, and theresulting crystals were collected by filtration to obtain 2.80 g (yield77.6%) of diphenylmethyl7-[2-(2-chloroacetamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate having a melting point of 129°-132° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1780, 1720, 1675.

NMR(d₆ -DMSO) ppm value: 2.44 (3H, s, --CH₃), 3.53 (2H, bs, C₂ -H), 3.88(3H, s, --OCH₃), 4.38 (2H, s, ClCH₂ --), 5.26 (1H, d, J=5 Hz, C₆ -H),5.55 ##STR503## 5.96 (1H, dd, J=5 Hz, J=8 Hz, C₇ -H), 6.92 (1H,s, >CH--), 7.00-7.63 ##STR504## 9.73 (1H, d, J=8 Hz, --CONH--).

In the same manner as above, the following compound was obtained:

Diphenylmethyl7-[2-(2-chloroacetamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[(3-chloro-1,2,4-triazolyl)methyl]-Δ³-cephem-4-carboxylate.

Melting point: 120°-124° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1780, 1720, 1675.

NMR(d₆ -DMSO) ppm value: 3.50 (2H, bs, C₂ -H), 3.90 (3H, s, --OCH₃),4.41 (2H, s, ClCH₂ --), 4.99-5.41 ##STR505## 5.98 (1H, dd, J=5 Hz, J=8Hz, C₇ -H), 6.96 (1H, s, >CH--), 7.03-7.67 ##STR506## 7.99 ##STR507##9.73 (1H, d, J=8 Hz, --CONH--).

(3) In 10 ml of N,N-dimethylformamide was dissolved 2.0 g of thediphenylmethyl7-[2-(2-chloroacetamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate obtained in above (2), and 0.27 g of thiourea wasadded thereto, after which the mixture was subjected to reaction at roomtemperature for 3 hours. After completion of the reaction, the reactionmixture was introduced into a mixed solvent of 20 ml of water and 30 mlof ethyl acetate, and the pH thereof was then adjusted to 7.0 withsodium hydrogen carbonate. The organic layer was separated, washedsuccessively with 15 ml of water and 15 ml of saturated aqueous solutionof sodium chloride and dried on anhydrous magnesium sulfate, after whichthe solvent was removed by distillation under reduced pressure. Diethylether was added to the residue, and the resulting crystals werecollected by filtration, to obtain 1.45 g (yield 81.0%) ofdiphenylmethyl7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[2-(5-methyl-1,2,3,4tetrazolyl)methyl]-Δ³-cephem-4-carboxylate having a melting point of 102°-105° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1778, 1720, 1660.

NMR(d₆ -DMSO) ppm value: 2.43 (3H, s, --CH₃), 3.45 (2H, bs, C₂ -H), 3.84(3H, s, --OCH₃), 5.29 (1H, d, J=5 Hz, C₆ -H), 5.52 ##STR508## 5.93 (1H,dd, J=5 Hz, J=8 Hz, C₇ -H, 6.78 ##STR509## 6.91 (1H, s, >CH--), 7.32##STR510## 9.64 (1H, d, J=8 Hz, --CONH--).

In the same manner as above, the following compound was obtained:

Diphenylmethyl7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[(3-chloro-1,2,4-triazolyl)methyl]-Δ³-cephem-4-carboxylate

Melting point: 118°-122° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1775, 1720, 1660.

NMR(d₆ -DMSO) ppm value: 3.42 (2H, bs, C₂ -H), 3.84 (3H, s, --OCH₃),4.99-5.39 ##STR511## 5.92 (1H, dd, J=5 Hz, J=8 Hz, C₇ -H), 6.77##STR512## 6.97 (1H, s, >CH--), 7.34 ##STR513## 8.01 ##STR514## 9.67(1H, d, J=8 Hz, --CONH--).

(4) The compound obtained in above (3) was subjected to reaction andtreatment in the same manner as in Example 17-(2) to obtain thecompounds shown in Table 20.

                                      TABLE 20                                    __________________________________________________________________________     ##STR515##                                                                   Compound (R.sup.2)                                                                           Melting point (°C.)                                     __________________________________________________________________________     ##STR516##    123-125 (decomp.)                                               ##STR517##    162 (decomp.)                                                  __________________________________________________________________________

EXAMPLE 30

By subjecting various starting compounds to the same reaction as inExample 29, the corresponding compounds shown in Table 21 were obtained.

                                      TABLE 21                                    __________________________________________________________________________     ##STR518##                                                                   R.sup.2        R.sup.2      R.sup.2                                           __________________________________________________________________________     ##STR519##                                                                                   ##STR520##                                                                                 ##STR521##                                        ##STR522##                                                                                   ##STR523##                                                                                 ##STR524##                                        ##STR525##                                                                                   ##STR526##                                                                                 ##STR527##                                        ##STR528##                                                                                   ##STR529##                                                                                 ##STR530##                                        ##STR531##                                                                                   ##STR532##                                                                                 ##STR533##                                        ##STR534##    NHCOCH.sub.3                                                                                ##STR535##                                        ##STR536##                                                                                   ##STR537##                                                                                 ##STR538##                                        ##STR539##                                                                                   ##STR540##                                                                                 ##STR541##                                        ##STR542##                                                                                   ##STR543##                                                     ##STR544##                                                                                   ##STR545##                                                    __________________________________________________________________________

The physical properties of these compounds were identical with those ofthe compounds produced in Example 21.

EXAMPLE 31

(1) In 50 ml of anhydrous methylene chloride was dissolved 3.70 g of2-[2-(benzyloxycarboxamido)-5-chlorothiazol-4-yl]-2-(syn)-methoxyiminoaceticacid, and 1.06 g of N-methylmorpholine was added to the solution, afterwhich the reaction mixture was cooled to -35° C. Then, 1.12 g of ethylchlorocarbonate was added thereto and the resulting mixture wassubjected to reaction at -30° C. to -20° C. for 2 hours, after which asolution of 4.37 g of diphenylmethyl 7-amino-3-acetamidomethyl-Δ³-cephem-4-carboxylate in 50 ml of anhydrous chloroform was droppedthereinto. The resulting mixture was subjected to reaction at -20° C. to-10° C. for 1 hour and then at room temperature for 3 hours. Aftercompletion of the reaction, the solvent was removed by distillationunder reduced pressure, and the residue thus obtained was dissolved in50 ml of ethyl acetate and 40 ml of water, after which the organic layerwas separated. Again, 40 ml of water was added to the organic layer andthe pH thereof was adjusted to 1.5 with 2N hydrochloric acid withice-cooling. The organic layer was separated and dried on anhydrousmagnesium sulfate. The solvent was removed by distillation under reducedpressure, and diethyl ether was added to the residue. The resultingcrystals were collected by filtration to obtain 6.50 g (yield 82.4%) ofdiphenylmethyl7-[2-{2-(benzyloxycarboxamido)-5-chlorothiazol-4-yl}-2-(syn)-methoxyiminoacetamido]-3-acetamidomethyl-Δ³-cephem-4-carboxylate having a melting point of 132°-136° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1780, 1720, 1680-1640.

NMR(d₆ -DMSO) ppm value: 1.85 ##STR546## 3.51 (2H, bs, C₂ -H), 3.71-4.35##STR547## 3.89 (3H, s, --OCH₃), 5.14 (1H, d, J=5 Hz, C₆ -H), 5.21##STR548## 5.86 (1H, dd, J=5 Hz, J=8 Hz, C₇ -H), 6.88 (1H, s, >Ch--),6.98-7.67 ##STR549## 7.78-8.21 (1H, m, --NHCO--), 9.69 (1H, d, J=8 Hz,--CONH--).

(2) In 15 ml of anisole was dissolved 0.79 g of diphenylmethyl7-[2-{2-(benzyloxycarboxamido)-5-chlorothiazol-4-yl}-2-(syn)-methoxyiminoacetamido]-3-acetamidomethyl-Δ³-cephem-4-carboxylate, and 1.33 g of aluminum chloride was added to theresulting solution with ice-cooling, after which the resulting mixturewas subjected to reaction at 5°-10° C. for 2 hours. After completion ofthe reaction, the reaction mixture was added to 30 ml of iced water andthe pH thereof was adjusted to 7.5 with sodium hydrogen carbonate, afterwhich the insoluble matter was removed by filtration. The filtrate waswashed with 30 ml of ethyl acetate, and 50 ml of methyl ethyl ketone wasadded thereto, after which the pH was adjusted to 2.0 with 2Nhydrochloric acid. The organic layer was separated, washed with 30 ml ofsaturated aqueous solution of sodium chloride and dried on anhydrousmagnesium sulfate. The solvent was removed by distillation under reducedpressure, and diethyl ether was added to the residue. The resultingcrystals were collected by filtration, to obtain 0.37 g (yield 75.7%) of7-[2-(2-amino-5-chloro-thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-acetamidomethyl-Δ³-cephem-4-carboxylic acid having a melting pint of 148°-152° C.(decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1770, 1710, 1680-1620.

NMR(d₆ -DMSO) ppm value: 1.83 (3H, s, --COCH₃), 3.42 (2H, bs, C₂ -H),3.84 (3H, s, --OCH₃), 3.70-4.22 ##STR550## 5.02 (1H, D, J=5 Hz, C₆ -H),5.67 (1H, d, J=5 Hz, C₇ -H), 7.85-8.21 (1H, m, --NHCO--), 9.46 (1H, d,J=8 Hz, --CONH--).

EXAMPLE 32

(1) The same reaction and treatment as in Example 18-(1) and (2) wererepeated, except that the2-(2-tert.-amyloxycarboxamidothiazol-4-yl)-2-(syn)-methoxyiminoaceticacid was replaced with a 2-(thiazol-4-yl)-2-(syn)-methoxyiminoaceticacid. As a result, the compounds shown in Table 22 and Table 23 wereobtained.

                                      TABLE 22                                    __________________________________________________________________________     ##STR551##                                                                            Melting                                                                             IR(KBr)                                                                 point cm.sup.-1 :                                                    R.sup.2  (°C.)                                                                        ν.sub.C═O                                                                   NMR(CDCl.sub.3) ppm value:                                __________________________________________________________________________     ##STR552##                                                                            102-104 (decomp.)                                                                   1785, 1730, 1680                                                                    ##STR553##                                                                   (1H, d, J= 5Hz, C.sub.6H), 5.88 (1H, dd, J=5Hz,                                ##STR554##                                                                    ##STR555##                                                                    ##STR556##                                                                    ##STR557##                                                ##STR558##                                                                            106-109 (decomp.)                                                                   1780, 1730, 1630                                                                    ##STR559##                                                                   5.92 (1H, dd, J=6Hz, J=8Hz, C.sub.7H), 6.89 (1H,                               ##STR560##                                                                    ##STR561##                                                                    ##STR562##                                               __________________________________________________________________________

                                      TABLE 23                                    __________________________________________________________________________     ##STR563##                                                                   (syn isomer)                                                                           Melting                                                                             IR(KBr) cm.sup.-1 :                                            R.sup.2  point (°C.)                                                                  ν.sub.C═O                                                                      NMR(d.sub.6 -DMSO) ppm value:                          __________________________________________________________________________     ##STR564##                                                                            130-140 (decomp.)                                                                   1780, 1715, 1670                                                                       ##STR565##                                             ##STR566##                                                                            129-134 (decomp.)                                                                   1780, 1720, 1675                                                                       ##STR567##                                                                    ##STR568##                                            __________________________________________________________________________

EXAMPLE 33

(1) In 30 ml of N,N-dimethylformamide was dissolved 6.13 g of7-[2-(2-tert.-amyloxycarboxamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[(3-chloro-1,2,4-triazolyl)]methyl-Δ³-cephem-4-carboxylic acid, and 1 g of triethylamine and 2.9 g ofpivaloyloxymethyl iodide were added to the resulting solution withice-cooling, after which the resulting mixture was subjected to reactionfor 30 minutes. After completion of the reaction, the reaction mixturewas introduced into a mixed solvent of 300 ml of water and 300 ml ofethyl acetate, and the pH thereof was adjusted to 7.0 with sodiumhydrogen carbonate. Then, the organic layer was separated, washedsuccessively with 100 ml of water and 100 ml of saturated aqueoussolution of sodium chloride and dried on anhydrous magnesium sulfate,after which the solvent was removed by distillation under reducedpressure. Diisopropyl ether was added to the residue, and the resultingcrystals were collected by filtration, thoroughly washed withdiisopropyl ether and dried, to obtain 6.6 g (yield 90.8 %) ofpivaloyloxymethyl7-[2-(2-tert.-amyloxycarboxamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[(3-chloro-1,2,4-triazolyl)methyl]-Δ³-cephem-4-carboxylate.

IR(KBr) cm⁻¹ : ν_(C)═O 1790, 1750, 1720, 1675.

NMR(CDCl₃) ppm value: 0.96 (3H, t, J=7 Hz, --CH₂ CH₃), 1.30 (9H, s,--C(CH₃)₃), 1.57 ##STR569## 1.91 (2H, q, J=7 Hz, --CH₂ CH₃), 3.33 (2H,bs, C₂ -H), 4.02 (3H, s, --OCH₃), 4.89-5.34 ##STR570## 5.70-6.27 (3H, m,--COOCH₂ --, C₇ -H), 7.14 ##STR571## 7.90 ##STR572## 9.31 (1H, d, J=8Hz, --CONH--).

(2) In 33 ml of trifluoroacetic acid was dissolved 6.6 g ofpivaloyloxymethyl7-[2-(2-tert.-amyloxycarboxamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[(3-chloro-1,2,4-triazolyl)methyl]-Δ³-cephem-4-carboxylate, and the resulting solution was subjected toreaction at room temperature for 30 minutes. After completion of thereaction, the solvent was removed by distillation under reducedpressure, and 80 ml of water and 80 ml of ethyl acetate were added tothe residue, after which the pH of the resulting solution was adjustedto 7.0 with sodium hydrogen carbonate with ice-cooling. The organiclayer was separated and dried on anhydrous magnesium sulfate, and asolution of dry hydrogen chloride in diethyl ether was added theretowith ice-cooling and with stirring, upon which a white colored powderwas deposited. It was collected by filtration, thoroughly washed withdiethyl ether and dried to obtain 5.2 g (yield 88.2%) of hydrochlorideof pivaloyloxymethyl7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[(3-chloro-1,2,4-triazolyl)methyl]-Δ³-cephem-4-carboxylate having a melting point of 134°-136° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1790, 1755, 1680.

NMR(d₆ -DMSO) ppm value: 1.17 (9H, s, --C(CH₃)hd 3), 3.49 (2H, bs, C₂-H), 3.93 (3H, s, --OCH₃) 4.95-5.40 ##STR573## 5.60-6.02 (3H, m,--COOCH₂ --, C₇ -H), 6.91 ##STR574## 8.00 ##STR575## 8.83 (1H, d, J=9Hz, --CONH--).

EXAMPLE 34

(1) In 20 ml of N,N-dimethylformamide was suspended 2.96 g of7-amino-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylic acid. Then, the suspension was converted to asolution by adding 1.1 g of triethylamine with ice-cooling. Then, 2.7 gof pivaloyloxymethyl iodide was added to the solution, and the resultingmixture was subjected to reaction at 0°-5° C. for 1 hour. Aftercompletion of the reaction, the reaction mixture was introduced into amixed solvent of 250 ml of water and 200 ml of ethyl acetate, and the pHthereof was adjusted to 7.0 with sodium hydrogen carbonate. Afterremoving the insoluble matter, the organic layer was separated and driedon anhydrous magnesium sulfate, and then the solvent was removed bydistillation under reduced pressure. After washing the residue withdiethyl ether, the residue was dissolved in 30 ml of ethyl acetate, anda solution of 1 g of dry hydrogen chloride in 30 ml of diethyl ether wasadded to the resulting solution with ice-cooling and with stirring. Thedeposited crystals were collected by filtration, thoroughly washed withdiethyl ether and then recrystallized from chloroform to obtain 2.72 g(yield 60.9%) of hydrochloride of pivaloyloxymethyl7-amino-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate having a melting point of 149°-151° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1773, 1741, 1730.

NMR(d₆ -DMSO) ppm value: 1.18 (9H, s, --C(CH₃)₃), 2.44 (3H, s, --CH₃),3.60 (2H, s, C₂ -H), 5.23 (2H, s, C₆ -H, C₇ -H), 5.62 ##STR576##5.78-5.92 (2H, m, --COOCH₂ O--).

By subjecting various starting compounds to the same reaction as above,the corresponding compounds shown in Table 24 and Table 25 wereobtained.

                                      TABLE 24                                    __________________________________________________________________________     ##STR577##                                                                                                   d.sub.6 -DMSO*                                Compound    Melting                                                                             IR(KBr) NMR   CDCl.sub.3 **                                                                         ppm value:                            R.sup.1     point (°C.)                                                                  cm.sup.-1 : ν.sub.C═O                                                                CD.sub.3 OD***                                                                              Note (treatment)                __________________________________________________________________________     ##STR578## --    1775, 1758                                                                             ##STR579##         Column chromatography (Wako                                                   ilica gel C-200; developing                                                   sol- vent, benzene:ethyl                                                      acetate = 3:1)                                            2.02 (2H, bs, NH.sub.2), 2.51 (3H,                                            s, CH.sub.3), 3.33 (2H, bs, C.sub.2H),                                         ##STR580##                                                                   4.90 (2H, bs, C.sub.6H, C.sub.7H), 5.61                                        ##STR581##                                                                    ##STR582##                                                                   **                                                   ##STR583##  98-101                                                                             1788, 1740                                                                             ##STR584##         Column chromatography (Wako                                                   ilica gel C-200; developing                                                   sol- vent, benzene:ethyl                                                      acetate = 3:1)                                             ##STR585##                                                                    ##STR586##                                                                   **                                                  ****        135-137                                                                             1800, 1735                                                                            1.14 (9H, s, C(CH.sub.3).sub.3),                                                                  Oxalic acid was added to                                                      ethyl                            ##STR587## (decomp.)                                                                                    ##STR588##         acetate solution to form                                                      oxalate.                                                   ##STR589##                                                                   C.sub.2H), 4.86 (1H, d, J=6Hz,                                                C.sub.6H), 5.06 (1H, d, J=6Hz,                                                 ##STR590##                                                                    ##STR591##                                                                   7.03 (3H, bs, H.sub.3.sup.⊕N)                                             *                                                   ****        125-130                                                                             1790, 1780                                                                             ##STR592##         Oxalic acid was added to                                                      ethyl                           CH.sub.2 OCH.sub.2 CH.sub.3                                                               (decomp.)     2.47 (3H, s, CH.sub.3), 3.27 (2H,                                                                 acetate solution to form                                                      oxalate.                                                  bs, C.sub.2H), 3.55 (2H, q, J-7Hz,                                             ##STR593##                                                                    ##STR594##                                                                   ***                                                  ##STR595## 107-110 (decomp.)                                                                   1785, 1735                                                                             ##STR596##         Oxalic acid was added to                                                      ethyl acetate solution to                                                     form oxalate.                                              ##STR597##                                                                   C.sub.2H), 4.96 (1H, d, J=6Hz,                                                C.sub.6H), 5.11 (1H, d, J=6Hz,                                                 ##STR598##                                                                   5.82 (2H, s, COOCH.sub.2 O), 7.66                                              ##STR599##                                                                   *                                                   ****        117-120                                                                             1780, 1750                                                                             ##STR600##         Oxalic acid was added in                                                      ethyl                            ##STR601## (decomp.)                                                                                    ##STR602##         acetate solution to form                                                      oxalate.                                                   ##STR603##                                                                    ##STR604##                                                                   (2H, bs, C.sub.2H), 4.96 (1H, d,                                              J=6Hz, C.sub.6H), 5.14 (1H, d,                                                J=6Hz, C.sub.7H), 5.42 (2H, bs,                                                ##STR605##                                                                    ##STR606##                                                                   *                                                    ##STR607## --    1780, 1758                                                                             ##STR608##         Column chromatography (Wako                                                   ilica gel C-200; developing                                                   sol-                                                       ##STR609##         vent, benzene:ethyl acetate                                                   = 5:1)                                                     ##STR610##                                                                    ##STR611##                                                                   3.32 (2H, bs, C.sub.2H), 4.14 (2H, t,                                          ##STR612##                                                                   (1H, d, J=5Hz, C.sub.6H), 4.91                                                (1H, d, J=5Hz, C.sub.7H), 5.44,                                               5.77 (2H, ABq, J=15Hz,                                                         ##STR613##                                                                    ##STR614##                                                                   **                                                  ****        118-120                                                                             1800, 1700                                                                            0.87 (3H, t, J=7Hz, Oxalic acid was added to                                                      ethyl                           CH.sub.2 O(CH.sub.2).sub.3 CH.sub.3                                                       (decomp.)                                                                                    ##STR615##         acetate solution to form                                                      oxalate                                                    ##STR616##                                                                    ##STR617##                                                                   (2H, bs, C.sub.2H), 3.64 (2H, t,                                               ##STR618##                                                                   5.00 (1H, d, J=5Hz, C.sub.6H),                                                5.17 (1H, d, J=5Hz, C.sub.7H),                                                5.44 (2H, s, OCH.sub.2 O),                                                     ##STR619##                                                                    ##STR620##                                                                   *                                                    ##STR621## --    1770, 1750                                                                             ##STR622##                                                                   2.20 (2H, s, NH.sub.2), 2.60 (3H,                                              ##STR623##                                                                   C.sub.2H), 4.98 (1H, d, J=5Hz,                                                C.sub.6H), 5.11 (1H, d, J=5Hz,                                                 ##STR624##                                                                    ##STR625##                                                                   **                                                  __________________________________________________________________________     Note:                                                                         **** Oxalate                                                             

                                      TABLE 25                                    __________________________________________________________________________     ##STR626##                                                                    R.sup.1Compound                                                                         point (°C.)Melting                                                            ν.sub.C═O IR(KBr) cm.sup.-1 :                                                 ##STR627##        Note (treatment)                   __________________________________________________________________________     ##STR628##                                                                             152-155 (decomp.)                                                                   1803, 1750                                                                             ##STR629##       Oxalic acid was added to ethyl                                                acetate solution to form                                                      oxalate.                             ##STR630##                                                                             146-148                                                                             1778, 1720                                                                             ##STR631##       Column chromatography (Wako                                                   silica gel C-200; developing                                                  solvent, benzene:ethyl acetate                                                = 3:1)                                                       ##STR632##                                            ##STR633##                                                                              67-70                                                                              1780, 1760                                                                             ##STR634##       Column chromatography (Wako                                                   silica gel C-200; developing                                                  solvent, benzene:ethyl acetate                                                = 3:1)                                                       ##STR635##                                           *3 CH.sub.2 O(CH.sub.2).sub. CH.sub.3                                                   128-135                                                                             1773, 1720                                                                             ##STR636##       Oxalic acid was added to ethyl                                                acetate solution to form                                                      oxalate.                                                     ##STR637##                                           __________________________________________________________________________     Note:                                                                         *Optical isomer                                                               *3 Oxalate                                                                    *4 Upper component                                                            *5 Lower component                                                       

EXAMPLE 35

To a mixed solvent of 8 ml of anhydrous methylene chloride and 2.2 ml ofN,N-dimethylacetamide was added 3.7 g of phosphorus oxychloride at 0°-5°C., and the resulting mixture was subjected to reaction at thattemperature for 30 minutes. Then, the reaction mixture was cooled to-15° C. to -10° C., and 2.4 g of2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid was addedthereto, and the resulting mixture was subjected to reaction at thattemperature for 20 minutes. Then, a solution of 4.47 g of hydrochlorideof pivaloyloxymethyl7-amino-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate and 1.01 g of triethylamine in 20 ml of anhydrousmethylene chloride was dropped into the above-mentioned reaction mixtureat -10° C. After the dropping, the mixture was subjected to reaction at-10° C. for 30 minutes, at 0° C. for 30 minutes and then at roomtemperature for 30 minutes. After completion of the reaction, thesolvent was removed by distillation under reduced pressure, and 50 ml ofwater and 50 ml of ethyl acetate were added to the residue, after whichthe pH thereof was adjusted to 7.0 with sodium hydrogen carbonate. Theorganic layer was separated, washed successively with 30 ml of water and30 ml of saturated aqueous solution of sodium chloride and dried onanhydrous magnesium sulfate. The solvent was removed by distillationunder reduced pressure, and diethyl ether was added to the residue. Theresulting crystals were collected by filtration to obtain 5.1 g (yield86%) of pivaloyloxymethyl7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl-Δ³-cephem-4-carboxylate having a melting point of 127°-128° C. (decomp.)

IR(KBr) cm⁻¹ : ν_(C)═O 1780, 1743, 1675.

EXAMPLE 36

By subjecting various starting compounds to the same reaction as inExample 33 or Example 35, the corresponding compounds shown in Table 26,Table 27 and Table 28 were obtained.

                                      TABLE 26                                    __________________________________________________________________________     ##STR638##                                                                            Melting                                                                             IR(KBr)                                                        Compound point cm.sup.-1 :                                                    R.sup.2  (°C.)                                                                        ν.sub.C═O                                                                   NMR(d.sub.6 -DMSO) ppm value                              __________________________________________________________________________     ##STR639##                                                                            144-148 (decomp.)                                                                   1790, 1750, 1675                                                                    ##STR640##                                                                   9.84 (1H, d, J=8Hz, CONH)                                  ##STR641##                                                                            119-123 (decomp.)                                                                   1780, 1740, 1670                                                                    ##STR642##                                                                   5.48-6.02 (3H, m, OCH.sub.2 O, C.sub.7H), 6.92 (1H,                           s,                                                                             ##STR643##                                                                   CONH).                                                     ##STR644##                                                                            144-146 (decomp.)                                                                   1780, 1745, 1660                                                                    ##STR645##                                                                    ##STR646##                                                                    ##STR647##                                                                    ##STR648##                                                ##STR649##                                                                            135-137 (decomp.)                                                                   1785, 1745, 1672                                                                    ##STR650##                                                                    ##STR651##                                                                    ##STR652##                                               NHCOCH.sub.3                                                                           133-135 (decomp.)                                                                   1780, 1740, 1680˜   1620                                                      ##STR653##                                                                   J=5Hz, C.sub.6H), 5.48-6.00 (3H, m, COOCH.sub.2,                               ##STR654##                                                                   7.78-8.09 (1H, m, NHCO), 9.45 (1H, d, J=8Hz,                                  CONH)                                                      ##STR655##                                                                            130-132 (decomp.)                                                                   1780, 1745, 1665                                                                    ##STR656##                                                                    ##STR657##                                                                    ##STR658##                                               __________________________________________________________________________     Note:                                                                         * Hydrochloride                                                          

                                      TABLE 27                                    __________________________________________________________________________     ##STR659##                                                                              Melting                                                                             IR(KBr)                                                      R.sup.1    point (°C.)                                                                  cm.sup.-1 : ν.sub.C═O                                                          NMR(d.sub.6 -DMSO) ppm value:                        __________________________________________________________________________    *CH.sub.3  154 (decomp.)                                                                       1785, 1730, 1655                                                                       ##STR660##                                                                   (3H, s, COOCH.sub.3), 3.96 (3H, s, OCH.sub.3),                                5.23 (1H, d,                                                                   ##STR661##                                                                    ##STR662##                                                                   9.88 (1H, d, J=8Hz, CONH)                             ##STR663##                                                                              121-124 (decomp.)                                                                   1780, 1745, 1670                                                                       ##STR664##                                                                   3.52 (2H, bs, C.sub.2H), 3.82 (3H, s,                                         OCH.sub.3), 5.19                                                               ##STR665##                                                                   5.78 (1H, dd, J=5Hz, J=8Hz, C.sub.7H), 5.83 (2H,                              s,                                                                             ##STR666##                                                                   NH.sub.2), 9.55 (1H, d, J=8Hz, CONH)                  ##STR667##                                                                              166-168 (decomp.)                                                                   1775, 1745, 1665                                                                       ##STR668##                                                                    ##STR669##                                                                    ##STR670##                                                                   (1H, d, J=8Hz, CONH)                                  ##STR671##                                                                              127-130 (decomp.)                                                                   1780, 1740, 1675                                                                       ##STR672##                                                                   C.sub.2H), 3.82 (3H, s, OCH.sub.3), 5.19 (1H, d,                              J=5Hz,                                                                         ##STR673##                                                                    ##STR674##                                                                    ##STR675##                                                                   NH.sub.2), 9.56 (1H, d, J=8Hz, CONH)                  ##STR676##                                                                              130-136 (decomp.)                                                                   1780, 1775, 1665                                                                       ##STR677##                                                                   (2H, bs, C.sub.2H), 3.85 (3H, s, OCH.sub.3),                                  4.16 (2H,                                                                      ##STR678##                                                                    ##STR679##                                                                    ##STR680##                                                                    ##STR681##                                          CH.sub.2 O(CH.sub.2).sub.3 CH.sub.3                                                      148-152                                                                             1785, 1730, 1675                                                                       ##STR682##                                                     (decomp.)                                                                                    ##STR683##                                                                    ##STR684##                                                                   bs, C.sub.2H), 3.87 (3H, s, OCH.sub.3), 5.23                                  (1H, d,                                                                       J=5Hz, C.sub.6H), 5.43 (2H, s, COOCH.sub.2 O),                                5.62 (2H,                                                                      ##STR685##                                                                    ##STR686##                                           ##STR687##                                                                              107-108                                                                             1780, 1760, 1670                                                                       ##STR688##                                                                   (2H, bs, C.sub.2H), 3.85 (3H, s, OCH.sub.3),                                  5.20 (1H,                                                                      ##STR689##                                                                   (2H, s, OCH.sub.2 O), 5.73-5.97 (1H, m,                                       C.sub.7H),                                                                     ##STR690##                                                                   (1H, d, J=9Hz, CONH)                                  ##STR691##                                                                              125-130 (decomp.)                                                                   1780, 1760, 1667                                                                       ##STR692##                                                                   bs, C.sub.2H), 3.86 (3H, s, OCH.sub.3), 4.11                                  (2H, t,                                                                        ##STR693##                                                                    ##STR694##                                                                    ##STR695##                                                                    ##STR696##                                                                   J=8Hz, CONH)                                          ##STR697##                                                                              128-135                                                                             1780, 1755, 1665                                                                       ##STR698##                                                                   C.sub.2H), 3.92 (3H, s, OCH.sub.3), 5.29 (1H, d,                              J=5Hz,                                                                         ##STR699##                                                                    ##STR700##                                                                    ##STR701##                                                                   NHCO)                                                __________________________________________________________________________     Note:-                                                                        *Hydrochloride-                                                          

                                      TABLE 28                                    __________________________________________________________________________     ##STR702##                                                                             Melting                                                                            IR(KBr)                                                                  point                                                                              cm.sup.-1 :                                                    R.sup.1   (°C.)                                                                       ν.sub.C═O                                                                   NMR(d.sub.6 -DMSO) ppm value:                             __________________________________________________________________________    CH.sub.2 O(CH.sub.2).sub.3 CH.sub.3                                                     125-130                                                                            1780                                                                                ##STR703##                                                              1722,                                                                               ##STR704##                                                              1670                                                                                ##STR705##                                                                   OCH.sub.3), 5.10 (1H, d, J=5Hz, C.sub.6H), 5.25 (1H,                          dd,                                                                           J=5Hz, J=8Hz, C.sub.7H), 5.30 (2H, s, COOCH.sub.2                             O),                                                                            ##STR706##                                                                    ##STR707##                                                                   (1H, d, J=8Hz, CONH)                                       ##STR708##                                                                             133-135                                                                            1778, 1755, 1670                                                                    ##STR709##                                                                    ##STR710##                                                                    ##STR711##                                                                    ##STR712##                                                                    ##STR713##                                                                    ##STR714##                                               __________________________________________________________________________     Note:                                                                         *Optical isomer                                                               *1 The upper component obtained in Table 24 was used as the starting          compound.                                                                

EXAMPLE 37

Reaction and treatment were carried out in the same manner as in Example33-(1) to obtain the compound shown in Table 29.

                                      TABLE 29                                    __________________________________________________________________________     ##STR715##                                                                            Melting                                                                             IR(KBr)                                                                 point cm.sup.-1 :                                                    R.sup.2  (°C.)                                                                        ν.sub.C═O                                                                   NMR(CDCl.sub.3) ppm value:                                __________________________________________________________________________     ##STR716##                                                                            65-81 (decomp.)                                                                     1785, 1750, 1675                                                                    ##STR717##                                                                   s, OCH.sub.2 O), 5.91 (1H, dd, J=5Hz, J=8Hz,                                  C.sub.7H),                                                                     ##STR718##                                                                   7.93 (1H, d, J=8Hz, CONH), 8.77 (1H, d, J=2Hz,                                 ##STR719##                                                ##STR720##                                                                            71-81 (decomp.)                                                                     1785, 1745, 1675                                                                    ##STR721##                                                                    ##STR722##                                                                   5.94 (1H, dd, J=5Hz, J=8Hz, C.sub.7H), 7.69 (1H, d,                            ##STR723##                                                                    ##STR724##                                               __________________________________________________________________________

EXAMPLE 38

A solution of 2.5 g of mesitylenesulfonic acid dihydrate in 20 ml ofethyl acetate was added to a solution of 5.93 g of pivaloyloxymethyl7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate in 50 ml of ethyl acetate. The deposited crystalswere collected by filtration, washed with ethyl acetate and dried toobtain 7.39 g (yield 93.2%) of mesitylenesulfonic acid salt ofpivaloyloxymethyl7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate having a melting point of 218°-220° C. (decomp.).

IR(KBr) cm⁻¹ : ν_(C)═O 1782, 1745, 1680. ##STR725##

EXAMPLE 39

Using pivaloyloxymethyl7-amino-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate, reaction and treatment were carried out in thesame manner as in Example 12-(1) and Example 28-(1) and (2) to obtainpivaloyloxymethyl7-[2-(2-aminothiazol-4-yl)-2-(syn)-hydroxyiminoacetamido]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate. Further, this compound was treated in ethylacetate with a solution of dry hydrogen chloride in diethyl ether toobtain hydrochloride of pivaloyloxymethyl7-[2-(2-aminothiazol-4-yl)-2-(syn)-hydroxyiminoacetamido]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylate having a melting point of 142°-145° C. (decomp.)

IR(KBr) cm⁻ ¹ : ν_(C)═O 1785, 1750, 1675.

NMR(d₆ -DMSO) ppm value: 1.20 (9H, s, --C(CH₃)₃), 2.49 ##STR726## 3.55(2H, bs, C₂ --H), 5.26 (1H, d, J=5 Hz, C₆ --H), 5.63 ##STR727##5.78-5.95 (3H, m, C₇ --H, --COOCH₂ O--), 6.84 ##STR728## 9.76 (1H, d,J=7 Hz, --CONH--).

PREPARATION EXAMPLE 1

According to the formulation shown below, the main ingredient waspreviously mixed and triturated with lactose. To the mixture was addedan aqueous solution of hydroxypropyl cellulose. The resulting mixturewas kneaded, dried and pulverized to obtain powder. The powder wasblended with magnesium stearate previously triturated with starch, andthen the resulting mixture was tabletted.

    ______________________________________                                        Formulation                                                                   ______________________________________                                        Hydrochloride of pivaloyloxymethyl                                                                   130    mg                                              7-[2-(2-aminothiazol-4-yl)-2-(syn)-                                           methoxyiminoacetamido]-3-[2-(5-                                               methyl-1,2,3,4-tetrazolyl)methyl]-                                            Δ.sup.3 -cephem-4-carboxylate                                           Lactose                20     mg                                              Starch                 44     mg                                              Hydroxypropyl cellulose                                                                              5.4    mg                                              Magnesium stearate     0.6    mg                                                                     200    mg/tablet                                       ______________________________________                                    

By using other compounds in place of the aboved compound, tablets can beobtained similarly.

PREPARATION EXAMPLE 2

According to the formulation mentioned below, a portion of starch andmagnesium stearate were mixed and triturated, and the trituration thusobtained was mixed with the residual part of starch, hydroxypropylcellulose and the main ingredient. The mixture thus obtained was formedinto capsules according to a conventional capsule packing process:

    ______________________________________                                        Formulation                                                                   ______________________________________                                        Hydrochloride of pivaloyloxymethyl                                                                   136    mg                                              7-[2-(2-aminothiazol-4-yl)-2-(syn)-                                           methoxyiminoacetamido]-3-[2-(5-                                               methyl-1,2,3,4-tetrazolyl)methyl]-                                            Δ.sup.3 -cephem-4-carboxylate                                           Starch                 54     mg                                              Hydroxypropyl cellulose                                                                              6      mg                                              Magnesium stearate     4      mg                                                                     200    mg/capsule                                      ______________________________________                                    

By using other compounds in place of the above-mentioned compound,capsule preparations can be obtained similarly.

PREPARATION EXAMPLE 3

According to the formulation shown below, the main ingredient waspreviously mixed and triturated with lactose. To the mixture was addedan aqueous solution of hydroxypropyl cellulose. The resulting mixturewas kneaded, dried and pulverized to obtain powder. The powder wasblended with magnesium stearate previously triturated with starch, andthen the resulting mixture was tabletted.

    ______________________________________                                        Formulation                                                                   ______________________________________                                        Mesitylenesulfonic acid salt of                                                                     130    mg                                               pivaloyloxymethyl 7-[2-(2-                                                    aminothiazol-4-yl)-2-(syn)-                                                   methoxyiminoacetamido]-3-[2-(5-                                               methyl-1,2,3,4-tetrazolyl)methyl]-                                            Δ.sup.3 -cephem-4-carboxylate                                           Lactose               20     mg                                               Starch                44     mg                                               Hydroxypropyl cellulose                                                                             5.4    mg                                               Magnesium stearate    0.6    mg                                                                     200    mg/tablet                                        ______________________________________                                    

By using other compounds in place of the above-mentioned compound,tablets can be obtained similarly.

PREPARATION EXAMPLE 4

According to the formulation mentioned below, a portion of starch andmagnesium stearate were mixed and triturated, and the trituration thusobtained was mixed with the residual part of starch, hydroxypropylcellulose and the main ingredient. The mixture thus obtained was formedinto capsules according to a conventional capsule packing process:

    ______________________________________                                        Formulation                                                                   ______________________________________                                        Mesitylenesulfonic acid salt                                                                        136    mg                                               of pivaloyloxymethyl 7-[2-(2-                                                 aminothiazol-4-yl)-2-(syn)-                                                   methoxyiminoacetamido]-3-[2-(5-                                               methyl-1,2,3,4-tetrazolyl)-                                                   methyl]-Δ.sup.3 -cephem-4-carboxylate                                   Starch                54     mg                                               Hydroxypropyl cellulose                                                                             6      mg                                               Magnesium stearate    4      mg                                                                     200    mg/capsule                                       ______________________________________                                    

By using other compounds in place of the above-mentioned compound,capsule preparations can be obtained similarly.

PREPARATION EXAMPLE 5

A mixture of sodium hydrogen carbonate with7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-[2-(5-methyl-1,2,3,4-tetrazolyl)methyl]-Δ³-cephem-4-carboxylic acid was treated in a conventional manner to obtaina freeze-dried and sterilized sodium salt. One gram (potency) of thesodium salt was dissolved in 20 ml of physiological saline solution toobtain an injection.

PREPARATION EXAMPLE 6

One gram (potency) of the freeze-dried product obtained in PreparationExample 5 was dissolved in 4 ml of 0.5% (W/V) aqueous lidocainehydrochloride solution to obtain a dilutable injection.

PREPARATION EXAMPLE 7

One gram (potency) of the freeze-dried product obtained in PreparationExample 5 was dissolved into 20 ml of 5% glucose solution to obtain aninjection.

Moreover, the other compounds (free carboxylic acids) of this inventionrepresented by the formula [I] can also be formed into the correspondingfreeze-dried products (sodium salts) or injections by processing them inthe same manner as in Preparation Examples 5-7.

What is claimed is:
 1. 7-(Substituted or unsubstitutedamino)-3-substituted methyl-Δ³ -cephem-4-carboxylic acid represented bythe following formula or a salt thereof: ##STR729## wherein R¹represents a hydrogen atom or a carboxyl-protecting group; R^(2b)represents a 2-(1,2,3,4-tetrazolyl) group, attached to the exomethylenegroup at the 3-position of the cephem ring through a carbon-nitrogenbond, which may be substituted by one substitutent selected from thegroup consisting of halogen, C₁₋₁₄ alkyl, benzyl, phenethyl,4-methylbenzyl, naphthylmethyl, phenyl, naphthyl, indanyl, C₂₋₁₀alkenyl, hydroxyl, protected hydroxyl, oxo, C₁₋₁₄ alkylthio, nitro,cyano, amino, protected amino, C₁₋₁₄ alkylamino, di-C₁₋₁₄ alkylamino,C₁₋₁₂ acyl, C₁₋₁₂ acyl-C₁₋₁₄ alkyl, carboxyl, protected carboxyl,carbamoyl, amino-C₁₋₁₄ alkyl, N-C₁₋₁₄ alkylamino-C₁₋₁₄ alkyl,N,N-di-C₁₋₁₄ alkylamino-C₁₋₁₄ alkyl, hydroxy-C₁₋₁₄ alkyl,hydroxyimino-C₁₋₁₄ alkyl, C₁₋₁₄ alkoxy-C₁₋₁₄ alkyl, carboxy-C₁₋₁₄ alkyl,C₁₋₁₄ alkoxy-C₁₋₁₄ alkyl, benzyloxycarbonyl-C₁₋₁₄ alkyl,phenethyloxycarbonyl-C₁₋₁₄ alkyl, 4-methylbenzyloxycarbonyl-C₁₋₁₄ alkyl,naphthylmethyloxycarbonyl-C₁₋₁₄ alkyl, sulfo-C₁₋₁₄ alkyl, sulfo,sulfamoyl-C₁₋₁₄ alkyl, sulfamoyl, carbamoyl-C₁₋₁₄ alkyl, carbamoyl-C₂₋₁₀alkenyl and N-hydroxycarbamoyl-C₁₋₁₄ alkyl; R¹⁰ represents an aminogroup or a protected amino group represented by the formula, ##STR730##or by the formula, ##STR731## in which R¹¹, R¹², R¹³, R¹⁴ and R¹⁵, whichmay be identical or different, are hydrogen atoms or C₁₋₁₄ alkyl, C₂₋₁₀alkenyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, phenyl, naphthyl, indanyl,benzyl, phenethyl, 4-methylbenzyl, naphthylmethyl, furyl, thienyl,pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, thiadiazolyl, oxadiazolyl, thiatriazolyl, oxatriazolyl,triazolyl, tetrazolyl, pyridyl, 3-(2-methyl-4-pyrrolinyl),3-(4-pyrrolinyl), N-(methylpiperidinyl), quinolyl, phenazinyl,1,3-benzodioxolanyl, benzofuryl, benzothienyl, benzoxazolyl,benzthiazolyl, coumarinyl or acyl groups, which acyl can be derived fromformic acid, acetic acid, propionic acid, butanoic acid, isobutanonicacid, pentanoic acid, methoxyacetic acid, methylthioacetic acid, acrylicacid, crotonic acid, cyclohexanoic acid, cyclopentaneacetic acid,cyclohexaneacetic acid, cyclohexanepropionic acid orcyclohexadieneacetic acid; and B represents a hydrogen atom or a C₁₋₅alkoxy group.
 2. 7-(Substituted or unsubstituted amino)-3-substitutedmethyl-Δ³ -cephem-4-carboxylic acid or a salt thereof according to claim1, wherein B is a hydrogen atom.
 3. 7-(Substituted or unsubstitutedamino)-3-substituted methyl-Δ³ -cephem-4-carboxylic acid or a saltthereof according to claim 2, wherein R^(2b) is a 2-(1,2,3,4-tetrazolyl)group which may optionally be substituted by one substituent selectedfrom the group consisting of halogen, C₁₋₁₄ alkyl, hydroxyl, protectedhydroxyl, benzyl, phenethyl, 4-methylbenzyl, naphthylmethyl, C₁₋₁₄alkythio, cyano, amino, protected amino, carboxyl, protected carboxyl,C₁₋₁₄ alkoxy-C₁₋₁₄ alkyl, amino-C₁₋₁₄ alkyl, N-C₁₋₁₄ alkylamino-C₁₋₁₄alkyl, C₁₋₁₂ acyl, phenyl, naphthyl, indanyl and C₁₋₁₄alkoxycarbonyl-C₁₋₁₄ alkyl.
 4. 7-(Substituted or unsubstitutedamino)-3-substituted methyl-Δ³ -cephem-4-carboxylic acid or a saltthereof according to claim 3, wherein R¹⁰ is an amino group. 5.7-(Substituted or unsubstituted amino)-3-substituted methyl-Δ³-cephem-4-carboxylic acid or a salt thereof according to claim 4,wherein R^(2b) is 2-(5-methyl-1,2,3,4-tetrazolyl),2-(5-acetamido-1,2,3,4-tetrazolyl),2-(5-ethoxycarbonylmethyl-1,2,3,4-tetrazolyl),2-(5-phenyl-1,2,3,4-tetrazolyl, 2-(1,2,3,4-tetrazolyl),2-(5-bromo-1,2,3,4-tetrazolyl), 2-(5-methylthio-1,2,3,4-tetrazolyl),2-(5-amino-1,2,3,4-tetrazolyl), 2-(5-ethyl-1,2,3,4-tetrazolyl) or2-(5-ethoxycarbonyl-1,2,3,4-tetrazolyl).